CN103347856A - Multifunctional nitroxide derivatives and uses thereof - Google Patents

Abstract

The present invention provides multifunctional nitroxide derivatives comprising a potassium channel opener and a reactive oxygen species (ROS) degradation catalyst that can act as an anti-oxidant, as well as pharmaceutical compositions comprising them. The multifunctional compounds and pharmaceutical compositions of the invention are useful for treatment of diseases, disorders or conditions associated with oxidative stress or endothelial dysfunction.

Description

Multifunctional nitrogen oxygen derivative and uses thereof

Technical field

What the present invention relates to comprise potassium channel openers has a superoxide ion (O₂^-) catalyzed degradation character compound and relate to the pharmaceutical composition that comprises it.These compounds are used for the treatment of, prevention and/or processing disease, illness and the symptom relevant with oxidative stress or endothelial function disturbance.

Background technology

By the redox of ischemia-reperfusion or inflammation-induced stress experimental model in, the opener of the potassium channel regulated of display line plastochondria ATP-provides cytoprotection.Yet, to plastosome but not sarolemma K⁺The specificity of-ATP passage is most important to eliminating the hypotensive risk of general.

Consider at therapeutic administration antioxidant or K⁺The shown benefit that goes out in these pathologic conditions of-ATP channel opener, and more substantial benefit may from (i) remove simultaneously reactive oxygen species (ROS) and (ii) stimulation of endogenous mechanism (by open K⁺-ATP passage) stress to be protected from redox.If these act on the room and time and locate altogether, then will make this effect maximization.But this altogether location can not be by using two kinds of different pharmaceuticals (for example, independent K altogether⁺-ATP channel opener and antioxidant molecule) take place, because location in unpredictable their tissue distribution, metabolism, removing, drainage and the cell.

Brief summary of the invention

According to the present invention, pyrido dicyanodiamide part and 3-amino-2 have been found to use, 2,5, the conjugate of 5-tetramethylpyrrolidi-e base oxygen, a kind of free radical, more particularly, 2-cyano group-l-(l-hydroxyl-2,2,5,5-tetramethylpyrrolidi-e-3-yl)-the oxygen base of 3-(pyridin-3-yl) guanidine, be beneficial to very much treatment, prevent and/or handle various disease, illness or the symptom relevant with oxidative stress or endothelial function disturbance, for example Myocardial Ischemia Reperfusion Injury and renal ischaemia-reperfusion injury and acute chlorine suck damage.

In one aspect, therefore, the present invention relates to the multifunctional nitrogen oxygen derivative of formula I:

Wherein Y be N, CH or N (→ O),

Or its enantiomer, diastereomer, racemic modification or pharmacy acceptable salt, solvate or prodrug,

Wherein

A is the part that is connected to the general formula II of any carbon atom in pyridine, phenyl or the pyridine oxide ring by its end-NH group:

X does not exist or is-(CR₂R₂)_n-;

R₁Do not exist or be 1 to 5 substituting group, each substituting group be independently selected from halogen ,-CN ,-OH ,-NO₂,-N (R₆)₂,-OCF₃,-CF₃,-OR₆,-COR₆,-COOR₆,-CON (R₆)₂,-OCOOR₆,-OCON (R₆)₂,-(C₁-C₈) alkyl ,-(C₁-C₈) alkylidene group-COOR₆,-SR₆,-SO₂R₆,-SO₂N (R₆)₂Or-S (=O) R₆, wherein said-(C₁-C₈) alkyl and-(C₁-C₈) alkylidene group-COOR₆Optionally by-OH ,-OR₃,-OCF₃,-CF₃,-COR₃,-COOR₃,-OCOOR₃,-OCON (R₃)₂,-(C₁-C₈) alkylidene group-COOR₃,-CN ,-NH₂,-NO₂,-SH ,-SR₃,-(C₁-C₈) alkyl ,-O-(C₁-C₈) alkyl ,-N (R₃)₂,-CON (R₃)₂,-SO₂R₃Or-S (=O) R₃Replace, or two adjacent R₁The carbon atom formation 5-that group is connected with them or 6-unit's carbocyclic ring or heterocycle, (C₆-C₁₀) aryl or 6-to 10-unit heteroaryl;

Each R₂Be independently selected from H, halogen ,-OCF₃,-CF₃,-OR₇,-COR₇,-COOR₇,-OCOOR₇,-OCON (R₇)₂,-(C₁-C₈) alkylidene group-COOR₇,-CN ,-NO₂,-SH ,-SR₇,-(C₁-C₈) alkyl ,-N (R₇)₂,-CON (R₇)₂,-SO₂R₇, SO₂N (R₇)₂Or-S (=O) R₇Or two R₂The carbon atom that group is connected with them forms 5-or 6-unit's carbocyclic ring or heterocycle;

Each R₃Be independently selected from (C₁-C₈) alkyl, (C₂-C₈) thiazolinyl or (C₂-C₈) alkynyl;

R₄Be selected from H ,-COOR₇,-(C₁-C₈) alkylidene group-COOR₇,-CN ,-(C₁-C₈) alkyl or-CON (R₇)₂

R₅Be selected from H ,-OH ,-O-(C₁-C₈) alkyl ,-CO-(C₁-C₈) alkyl ,-COO-(C₁-C₈) alkyl ,-CN or-NH₂

Each R₆Be independently selected from H, (C₁-C₈) alkyl, (C₃-C₁₀) cycloalkyl, 4-12-unit heterocyclic radical, (C₆-C₁₄) aryl or-(C₁-C₈) alkylidene group-NH₂

Each R₇Be independently selected from H, (C₁-C₈) alkyl ,-(C₁-C₈) alkylidene group-NH₂, (C₃-C₁₀) cycloalkyl, 4-12-unit's heterocyclic radical or (C₆-C₁₄) aryl, wherein each (except H) is optionally by-OR₆,-COR₆,-COOR₆,-OCOOR₆,-OCON (R₆)₂,-(C₁-C₈) alkylidene group-COOR₆,-CN ,-NO₂,-SR₆,-(C₁-C₈) alkyl ,-N (R₆)₂,-CON (R₆)₂,-SO₂R₆Or-S (=O) R₆Replace; And

N isinteger 1 or 2.

In yet another aspect, the present invention relates to a kind of pharmaceutical composition, it comprises the multifunctional nitrogen oxygen derivative of formula I as defined above, or its enantiomer, diastereomer, racemic modification or pharmacy acceptable salt, solvate or prodrug, and pharmaceutically acceptable supporting agent.

Multifunctional nitrogen oxygen derivative of the present invention is used for the treatment of with pharmaceutical composition, prevention and/or processing disease, illness and the symptom relevant with oxidative stress with high-caliber reactive oxygen species (ROS).Therefore, in yet another aspect, the invention provides the multifunctional nitrogen oxygen derivative of general formula I as defined above, or its enantiomer, diastereomer, racemic modification or pharmacy acceptable salt, solvate or prodrug, to be used for the treatment of disease, illness or the symptom relevant with oxidative stress with high-caliber ROS.

In yet another aspect, the invention provides a kind of method that is used for the treatment of disease, illness or the symptom relevant with oxidative stress with high-caliber ROS, described method comprises the multifunctional nitrogen oxygen derivative to the general formula I as defined above of the individual administering therapeutic significant quantity that needs are arranged, or its enantiomer, diastereomer, racemic modification or pharmacy acceptable salt, solvate or prodrug.

The accompanying drawing summary

Fig. 1 shows measured mean arterial pressure (mmHg) in the rat of standing perfusion (I/R) damage (MIRI) model of myocardial ischemia-more as described in example 11 above, show whencompound 2 again the perfusion before with 1mg/kg intravenous injection (IV bolus), when lasting venoclysis was used in 2mg/kg/ hour then, do not produce the whole body ypotension.

Fig. 2 A-2B shows the histology protection thatcompound 2 provides in the MIRI rat model described in the embodiment 11, show whencompound 2 again the perfusion before with the 1mg/kg intravenous injection, when lasting venoclysis was used in 2mg/kg/ hour then, obviously reduce myocardium myeloperoxidase (MPO) (2A) and tissue infraction (2B) (p＜0.01 pair I/R+ vehicle; Every group of n=10 rat).By single factor ANOVA, carry out Bonferroni then and check afterwards and carry out multiple comparisons and come analytical results.Be the standard error (SEM) of mean value ± mean value of N animal with all values and text representation.

Fig. 3 A-3C has set forth MIRI, that is, serious myocyte's necrosis, edema and neutrophil infiltration stand as described in example 11 above coronary occlusion (20 minutes) and subsequently again the perfusion (2 hours) rat (3A); The sham-operation contrast, the rat (3B) of namely having stood the identical operative procedure except coronary occlusion; With stood identical operative procedure and utilizedcompound 2 with the 1mg/kg intravenous injection before the perfusion again, 2mg/kg/h continues the histology influence in the rat (3C) that venoclysis handles then.As shown,compound 2 weakens all histologic characteristicses in fact of the damage of being induced by MIRI significantly.

Fig. 4 A-4C demonstrates and before theperfusion compound 2 is being added in the mouse model of the renal ischaemia-reperfusion injury described in the embodiment 12, weaken rising (seeing Fig. 4 A and 4B respectively) and kidney myeloperoxidase (MPO) rising (p＜0.01 pair vehicle contrast) (4C) of blood plasma blood urea nitrogen (BUN) and creatinine significantly.

Fig. 5 A-5B has shown in the mouse model of acute chlorine suction damage (CILI), after chlorine exposes, peritoneal injection (IP) administered compound 2 (30mg/kg/ dosage in 0.5ml D5W), with respect to placebo (D5W), the MPO that reduces respectively in the male Balb/c mouse raises (showing that polymorphonuclear leukocyte (PMN) soaks into) (5A) and lung tissue damage (5B) 52% (p＜0.0001) and 43% (p＜0.001).

Fig. 6 has shown histology score, shows in salts solution to prepare, and at Cl₂Expose back 2 hours and 6 hours by thecompound 2 of peritoneal injection with the administration of 0.25ml volume, weaken injury of lung in the dose-dependently mode, every kind of dosage 3mg to 80mg (or every day 6mg to 160mg).Be the standard error (SEM) of mean value ± mean value of N animal with value representation.Histology score is: sham-operation/vehicle: mean value=0 (n=2 mouse,mark 0,0); Cl₂+ vehicle: mean value 3.2, SE0.37 (n=5,mark 2,3,3,4,4); Cl₂+ 80mg/kg:0.70, SE0.45 (n=5,mark 0,1,1,1,1.5); Cl₂+ 30mg/kg:1.4SE0.51 (n=5,mark 0,1,1,2,3); Cl₂+ 10mg/kg:2.2, SE0.37 (n=5,mark 1,2,2,3,3); Cl₂+ 3mg/kg:3.0, SE0.32 (n=5,mark 2,3,3,3,4).

Fig. 7 shows and to compare with salt solution vehicle group, injectscompound 2 to the administration of male Balb/c mouse by intraperitoneal and do not show any remarkably influenced to glucose level.

Detailed Description Of The Invention

The invention provides the compound of general formula I as defined above, be also referred to as " multifunctional nitrogen oxygen derivative " in the literary composition, reactive oxygen species (ROS) degradation catalyst that it comprises potassium channel openers and can be used as antioxidant.As used herein, term " reactive oxygen species (ROS) degradation catalyst " refers to can be used as the scavenging agent of superoxide or other ROS (comprising superoxide, hydroxyl, peroxynitrite salt, peroxycarbonate, hypochlorous acid and hydrogen peroxide), or the group of catalyze detoxification superoxide or other ROS.To preferentially remove or the antioxidant of catalyze detoxification superoxide is called " superoxide dismutase stand-in " (" SOD-stand-in ") or " superoxide dismutase dummy " (" SOD-dummy ").ROS superoxide, hydroxyl, peroxynitrite salt, peroxycarbonate, hypochlorous acid and hydrogen peroxide are considered to non-required biologically.This ROS degradation catalyst is nitroxyl free radical (NO^-).

Multifunctional nitrogen oxygen derivative of the present invention is used for prevention and treatment inflammatory and pours into disease, illness or symptom again.By potassium channel openers and covalently bound ROS degrading activity, compound of the present invention is guaranteed to add the decline that potassium channel openers is followed the ROS level simultaneously and spatially, and described ROS comprises peroxynitrite salt, peroxycarbonate, hydrogen peroxide, hydroxyl and its other oxygenant metabolite.

As used herein, term " halogen " comprises fluorine, chlorine, bromine and iodine, and is preferably preferred fluorine, chlorine or bromine.

As used herein, term " alkyl " means the straight or branched saturated hydrocarbyl with 1-8 carbon atom usually and comprises, for example, methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, sec-butyl, isobutyl-, the tertiary butyl, n-pentyl, 2,2-dimethyl propyl, n-hexyl, n-heptyl, n-octyl etc.(C preferably₁-C₆) alkyl, more preferably (C₁-C₄) alkyl, most preferable and ethyl.Term " thiazolinyl " and " alkynyl " mean straight chain and the branched hydrocarbyl that has 2-8 carbon atom and have two keys or triple bond respectively usually, and comprise vinyl, propenyl, 3-butene-1-Ji, 2-vinyl butyl, 3-octene-1-Ji etc. and proyl, 2-butyne-1-base, 3-pentyne-1-base etc.C preferably₂-C₆Thiazolinyl and alkynyl, more preferably C₂-C₄Thiazolinyl and alkynyl.

Term " alkylidene group " means the divalence straight or branched alkyl with 1-8 carbon atom usually, and comprise, for example, methylene radical, ethylidene, propylidene, butylidene, 2-methyl propylidene, pentylidene, 2-methyl butylidene, hexylidene, 2-methyl pentylidene, 3-methyl pentylidene, 2,3-dimethyl butylidene, inferior heptyl, octylene etc.(C preferably₁-C₆) alkylidene group, more preferably (C₁-C₄) alkylidene group, most preferably (C₁-C₂) alkylidene group.

As used herein, term " cycloalkyl " means list with 3-10 carbon atom-or dicyclo saturated hydrocarbyl, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, ring octyl group, adamantyl, dicyclo [3.2.1] octyl group, dicyclo [2.2.1] heptyl etc., it for example can be replaced by one or more alkyl.

As used herein, term " carbocyclic ring " saturated or unsaturated (that is, comprising at least one unsaturated link(age)) ring of referring to be formed by 3-10 carbon atom.Preferably 5-or 6-the unit carbocyclic ring, for example pentamethylene, cyclopentenes, hexanaphthene, tetrahydrobenzene etc.

Term " heterocycle " expression has the list of 4-12 atom-or many-encircle non-aromatic ring, it comprises at least one carbon atom and one to three, preferred 1-2 heteroatoms that is selected from sulphur, oxygen or nitrogen, and it can be saturated or undersaturated, that is, comprise at least one unsaturated link(age).Preferably 5-or 6-the unit heterocycle.As used herein, term " heterocyclic radical " refers to by remove hydrogen from any annular atoms from any monoradical as the heterocyclic derivatives that defines the literary composition.This group example includes, but not limited to piperidyl, 4-morpholinyl or pyrrolidyl.

Term " aryl " expression has the aromatic carbon ring base of 6-14 carbon atom, and it is formed by single ring or a plurality of condensation or by the ring of covalent linkage connection, such as, but not limited to, phenyl, naphthyl, phenanthryl and xenyl.Aryl is optionally replaced by one or more groups, and each group is independently selected from halogen (for example, F, Cl or Br), (C₁-C₈) alkyl ,-O-(C₁-C₈) alkyl ,-COO (C₁-C₈) alkyl ,-CN or NO₂

Term " heteroaryl " refers to that it contains 1 to 3, the individual heteroatoms that is selected from N, O and S of preferred 1-2 by single-or many-group that ring heteroaromatic ring is derived.When heteroaryl is monocycle, it is preferably 5-6-unit cyclic group, such as, but not limited to, pyrryl, furyl, thienyl, thiazinyl, pyrazolyl, pyrazinyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrimidyl, 1,2,3-triazinyl, 1,3,4-triazinyl and 1,3,5-triazinyl.Polyheteroaromatic preferably is made up of two rings, for example, but be not limited to, benzofuryl, isobenzofuran-base, benzothienyl, indyl, quinolyl, isoquinolyl, imidazo [1,2-α] pyridyl, benzimidazolyl-, benzothiazolyl, benzoxazolyl, pyrido [l, 2-a] pyrimidyl and 1,3-Ben Bing dioxin base.Heteroaryl can be substituted.Should be appreciated that when polyheteroaromatic was substituted, replacement can be in any one of carbocyclic ring and/or heterocycle.

In certain embodiments, multifunctional nitrogen oxygen derivative of the present invention is the compound of general formula I, and wherein Y is N, that is, wherein group A is connected to theposition 2,3,4 of pyridine ring, 5 or 6 compound.This concrete compounds shown in the table 1 is such compound, wherein A is connected to theposition 2,3 or 4 of pyridine ring, and (i) X does not exist, that is the oxygen base (being respectively formula Ia-1, Ia-2 or Ia-3) of 1-(1-hydroxyl pyrrolidine-3-yl)-3-(pyridine-2-yl) guanidine derivative, 1-(1-hydroxyl pyrrolidine-3-yl)-3-(pyridin-3-yl) guanidine derivative or 1-(1-hydroxyl pyrrolidine-3-yl)-3-(pyridin-4-yl) guanidine derivative; (ii) X is-(CR₂R₂)_n-, wherein n is 1, that is the oxygen base (being respectively formula Ia-4, Ia-5 or Ia-6) of 1-(1-hydroxy piperidine-4-yl)-3-(pyridine-2-yl) guanidine derivative, l-(l-hydroxy piperidine-4-yl)-3-(pyridin-3-yl) guanidine derivative or 1-(1-hydroxy piperidine-4-yl)-3-(pyridin-4-yl) guanidine derivative; Or (iii) X is-(CR₂R₂)_n-, wherein n is 2, that is the oxygen base (being respectively formula Ia-7, Ia-8 or Ia-9) of 1-(1-hydroxyl azepan-4-yl)-3-(pyridine-2-yl) guanidine derivative, 1-(1-hydroxyl azepan-4-yl)-3-(pyridin-3-yl) guanidine derivative or 1-(1-hydroxyl azepan-4-yl)-3-(pyridin-4-yl) guanidine derivative.This compounds is that wherein A is connected to theposition 3 of pyridine ring or those compounds of 4 more specifically.

Table 1: the multifunctional nitrogen oxygen derivative of formula Ia-1 to Ia-9

In other embodiments, multifunctional nitrogen oxygen derivative of the present invention is the compound of general formula I, and wherein Y is CH, that is, wherein group A is connected to the compound of the optional position of phenyl ring.This concrete compounds shown in the table 2 is such compound, and wherein (i) X does not exist, that is, and and the oxygen base (formula Ib-1) of l-(l-hydroxyl pyrrolidine-3-yl)-3-guanidines derivative; (ii) X is-(CR₂R₂)_n-, wherein n is 1, that is, and and the oxygen base (formula Ib-2) of 1-(1-hydroxy piperidine-4-yl)-3-guanidines derivative; Or (iii) X is-(CR₂R₂)_n-, wherein n is 2, that is, and and the oxygen base (formula Ib-3) of 1-(1-hydroxyl azepan-4-yl)-3-guanidines derivative.

Table 2: the multifunctional nitrogen oxygen derivative of formula Ib-1 to Ib-3

In other embodiments, multifunctional nitrogen oxygen derivative of the present invention is the compound of general formula I, wherein Y be N (→ O), that is, wherein group A is connected to theposition 2,3,4 of pyridine oxide ring, 5 or 6 compound.This concrete compounds shown in the table 3 is such compound, wherein A is connected to theposition 2,3 or 4 of pyridine oxide ring, and (i) X does not exist, that is the oxygen base (being respectively formula Ic-1, Ic-2 or Ic-3) of l-(l-hydroxyl pyrrolidine-3-yl)-3-(l-oxygen yl pyridines-2-yl) guanidine derivative, 1-(1-hydroxyl pyrrolidine-3-yl)-3-(l-oxygen yl pyridines-3-yl) guanidine derivative or 1-(1-hydroxyl pyrrolidine-3-yl)-3-(1-oxygen yl pyridines-4-yl) guanidine derivative; (ii) X is-(CR₂R₂)_n-, wherein n is 1, that is the oxygen base (being respectively formula Ic-4, Ic-5 or Ic-6) of 1-(1-hydroxy piperidine-4-yl)-3-(1-oxygen yl pyridines-2-yl) guanidine derivative, 1-(1-hydroxy piperidine-4-yl)-3-(1-oxygen yl pyridines-3-yl) guanidine derivative or 1-(1-hydroxy piperidine-4-yl)-3-(1-oxygen yl pyridines-4-yl) guanidine derivative; Or (iii) X is-(CR₂R₂)_n-, wherein n is 2, that is the oxygen base (being respectively formula Ic-7, Ic-8 or Ic-9) of 1-(1-hydroxyl azepan-4-yl)-3-(1-oxygen yl pyridines-2-yl) guanidine derivative, 1-(1-hydroxyl azepan-4-yl)-3-(l-oxygen yl pyridines-3-yl) guanidine derivative or 1-(1-hydroxyl azepan-4-yl)-3-(1-oxygen yl pyridines-4-yl) guanidine derivative.This compounds is that wherein A is connected to theposition 3 of pyridine ring or those compounds of 4 more specifically.

Table 3: the multifunctional nitrogen oxygen derivative of formula Ic-1 to Ic-9

According to the present invention, R₁There is not or represents 1 to 5 substituting group as defined above.Yet, should be appreciated that, therein Y be N or N (in → O) the situation, R₁The maximum quantity of group only is limited to 4.

In certain embodiments, the multifunctional nitrogen oxygen derivative of the present invention compound that is general formula I a-1 to Ia-9, compound or the compound of general formula I c-1 to Ic-9, the wherein R of general formula I b-1 to Ib-3₁Do not exist.

In other embodiments, the multifunctional nitrogen oxygen derivative of the present invention compound that is general formula I a-1 to Ia-9, compound or the compound of general formula I c-1 to Ic-9, the wherein R of formula Ib-1 to Ib-3₁Be 1,2,3,4 or 5, preferred 1 or 2, more preferably 1, each substituting group be independently selected from halogen ,-OH ,-CN ,-NO₂,-N (R₆)₂,-OR₆,-OCF₃,-CF₃,-COR₆,-COOR₆,-CON (R₆)₂,-OCOOR₆,-OCON (R₆)₂,-(C₁-C₈) alkyl ,-(C₁-C₈) alkylidene group-COOR₆,-SR₆,-SO₂R₆,-SO₂N (R₆)₂Or-S (=O) R₆, each R wherein₆Be H, (C independently₁-C₈) alkyl or-(C₁-C₈) alkylidene group-NH₂, preferred H.

In other embodiments, multifunctional nitrogen oxygen derivative of the present invention be general formula I a-1 to Ia-9 compound, the compound of general formula I b-1 to Ib-3 or the compound of general formula I c-1 to Ic-9, wherein two adjacent R₁The carbon atom formation 5-of the pyridine ring that group is connected with them or 6-unit's carbocyclic ring or heterocycle, (C₆-C₁₀) aryl or 6-to 10-unit heteroaryl.In these embodiments, in the general formula I A group in fact be connected to pyridine-, phenyl or pyridine oxide-part, this part is condensed into and is selected from 5-or 6-unit's carbocyclic ring or heterocycle, (C₆-C₁₀) monocyclic groups or the bicyclic radicals of aryl or 6-to 10-unit heteroaryl.The unrestricted example of this type of multifunctional nitrogen oxygen derivative comprises the compound of (i) general formula I, and wherein Y is N, and wherein group A is connected to 6,7, dihydro-5H-cyclopenta [b] pyridine, 6,7, dihydro-5H-cyclopenta [c] pyridine, 5,6,7,8-tetrahydroquinoline, 5,6,7,8-tetrahydroisoquinoline, 2,3 dihydro furan be [3,2-b] pyridine, 3 also, 4-dihydro-2H-pyrans also [3,2-b] pyridine, quinoline, isoquinoline 99.9, benzo [g] quinoline, benzo [g] isoquinoline 99.9,1,5-naphthyridines, 1,8-naphthyridines, pyrido [2,3-b] pyrazine or pyrido [3,2-g] quinolone part; The (ii) compound of general formula I, wherein Y is CH, wherein group A is connected to 2,3-dihydro-1H-indenes, 1,2,3,4-naphthane, 2,3-Dihydrobenzofuranes, chroman, naphthalene, anthracene, quinoline, quinoxaline or benzo [g] quinoline moiety; And the (iii) compound of general formula I, wherein Y be N (→ O), wherein group A is connected to l-oxygen base-6,7, dihydro-5H-cyclopenta [b] pyridine, 2-oxygen base-6,7, dihydro-5H-cyclopenta [c] pyridine, l-oxygen base-5,6,7,8-tetrahydroquinoline, 2-oxygen base-5,6,7, the 8-tetrahydroisoquinoline, 4-oxygen base-2,3 dihydro furan is [3,2-b] pyridine also, 5-oxygen base-3,4-dihydro-2H-pyrans also [3,2-b] pyridine, the 1-phenoxyl quinoline, 2-oxygen base isoquinoline 99.9,1-oxygen base benzo [g] quinoline, 2-oxygen base benzo [g] isoquinoline 99.9, the 1-Oxy-1, the 5-naphthyridines, the 1-Oxy-1, the 8-naphthyridines, 5-oxygen yl pyridines also [2,3-b] pyrazine or 1-oxygen yl pyridines [3,2-g] quinoline moiety also.

In certain embodiments, the multifunctional nitrogen oxygen derivative of the present invention compound that is general formula I a-1 to Ia-9, compound or the compound of general formula I c-1 to Ic-9, wherein each R of general formula I b-1 to Ib-3₂Be H.

In certain embodiments, the multifunctional nitrogen oxygen derivative of the present invention compound that is general formula I a-1 to Ia-9, compound or the compound of general formula I c-1 to Ic-9, wherein each R of general formula I b-1 to Ib-3₃Be (C independently₁-C₄) alkyl, preferred (C₁-C₂) alkyl, more preferably methyl.In these concrete embodiments, multifunctional nitrogen oxygen derivative of the present invention is such compound, wherein R₃Be identical.

In certain embodiments, the multifunctional nitrogen oxygen derivative of the present invention compound that is general formula I a-1 to Ia-9, compound or the compound of general formula I c-1 to Ic-9, the wherein R of general formula I b-1 to Ib-3₄Be H.

In certain embodiments, the multifunctional nitrogen oxygen derivative of the present invention compound that is general formula I a-1 to Ia-9, compound or the compound of general formula I c-1 to Ic-9, the wherein R of general formula I b-1 to Ib-3₅Be-CN.

In some specific embodiment, multifunctional nitrogen oxygen derivative of the present invention is the compound of general formula I, and wherein Y is N; A is connected to theposition 2,3,4,5 or 6 of pyridine ring; R₁Do not exist or 1 to 4 substituting group, each substituting group is halogen independently; X do not exist or-(CR₂R₂)_n-, wherein n is 1 or 2; Each R₂Be H; Each R₃Be (C independently₁-C₄) alkyl, preferred (C₁-C₂) alkyl, more preferably methyl; R₄Be H; And R₅Be-CN.In some more particular embodiment, R₁Being the unique substituting group that is connected to arbitrarily effective carbon atom in the pyridine ring, that is, is being the halogen that adjacent, alternate or relative position is connected to pyridine ring with respect to group A.In other more particular embodiment, R₁Represent 2 substituting groups, each substituting group is connected to arbitrarily effective carbon atom of pyridine ring independently,, is connected to two halogens of pyridine ring in relative to each other adjacent, alternate or relative position that is.(every kind of compound has three kinds of configurations to this concrete compounds described in the specification sheets among compound 4-7,11-14 and the 18-21 with the Arabic numerals 1-21 of runic sign at this paper, be designated a-c), wherein describe in their the complete chemical structure following table 4.

In some specific embodiment, multifunctional nitrogen oxygen derivative of the present invention is the compound of general formula I, and wherein Y is N; X does not exist; R₁Do not exist; R₂Be H; R₃It is methyl; And A is connected to theposition 2,3 or 4 of pyridine ring, that is, and and 2-cyano group-1-(1-hydroxyl-2,2,5,5-tetramethylpyrrolidi-e-3-yl)-3-(pyridine-2-yl) guanidine (compound 1); 2-cyano group-1-(1-hydroxyl-2,2,5,5-tetramethylpyrrolidi-e-3-yl)-3-(pyridin-3-yl) guanidine (compound 2); Or the oxygen base (compound 3) of 2-cyano group-1-(1-hydroxyl-2,2,5,5-tetramethylpyrrolidi-e-3-yl)-3-(pyridin-4-yl) guanidine.

In other specific embodiment, multifunctional nitrogen oxygen derivative of the present invention is the compound of general formula I, and wherein Y is N; X does not exist; R₁Be F, Cl or Br, be connected to the position 6 of pyridine ring; R₂Be H; R₃It is methyl; And A is connected to theposition 2,3,4 or 5 of pyridine ring, that is 2-cyano group-l-(6-fluorine pyridine-2-yl)-3-(l-hydroxyl-2,2,, 5,5-tetramethylpyrrolidi-e-3-yl) guanidine, 2-cyano group-l-(6-chloropyridine-2-yl)-3-(l-hydroxyl-2,2,5,5-tetramethylpyrrolidi-e-3-yl) guanidine or 2-cyano group-l-(6-bromopyridine-2-yl)-3-(l-hydroxyl-2,2,5,5-tetramethylpyrrolidi-e-3-yl) the oxygen base of guanidine (is respectively compound 4_a-4_c); 2-cyano group-l-(6-fluorine pyridin-3-yl)-3-(l-hydroxyl-2,2,5,5-tetramethylpyrrolidi-e-3-yl) guanidine, 2-cyano group-l-(6-chloropyridine-3-yl)-3-(l-hydroxyl-2,2,5,5-tetramethylpyrrolidi-e-3-yl) guanidine or 2-cyano group-l-(6-bromopyridine-3-yl)-3-(l-hydroxyl-2,2,5,5-tetramethylpyrrolidi-e-3-yl) the oxygen base of guanidine (is respectively compound 5_a-5_c); 2-cyano group-1-(6-fluorine pyridin-4-yl)-3-(1-hydroxyl-2,2,5,5-tetramethylpyrrolidi-e-3-yl) guanidine, 2-cyano group-1-(6-chloropyridine-4-yl)-3-(1-hydroxyl-2,2,5,5-tetramethylpyrrolidi-e-3-yl) guanidine or 2-cyano group-1-(6-bromopyridine-4-yl)-3-(1-hydroxyl-2,2,5,5-tetramethylpyrrolidi-e-3-yl) the oxygen base of guanidine (is respectively compound 6_a-6_c); Or 2-cyano group-1-(6-fluorine pyridine-5-yl)-3-(l-hydroxyl-2,2,5,5-tetramethylpyrrolidi-e-3-yl) guanidine, 2-cyano group-1-(6-chloropyridine-5-yl)-3-(l-hydroxyl-2,2,5,5-tetramethylpyrrolidi-e-3-yl) guanidine or 2-cyano group-1-(6-bromopyridine-5-yl)-3-(l-hydroxyl-2,2,5,5-tetramethylpyrrolidi-e-3-yl) the oxygen base of guanidine (is respectively compound 7_a-7_c).

In other specific embodiment, multifunctional nitrogen oxygen derivative of the present invention is the compound of general formula I, and wherein Y is N; X is-(CR₂R₂)_n-, wherein n is 1; R₁Do not exist; R₂Be H; R₃It is methyl; And A is connected to theposition 2,3 or 4 of pyridine ring, that is, and and the oxygen base (compound 8) of 2-cyano group-1-(1-hydroxyl-2,2,6,6-tetramethyl piperidine-4-yl)-3-(pyridine-2-yl) guanidine; The oxygen base (compound 9) of 2-cyano group-1-(1-hydroxyl-2,2,6,6-tetramethyl piperidine-4-yl)-3-(pyridin-3-yl) guanidine; Or the oxygen base (compound 10) of 2-cyano group-1-(1-hydroxyl-2,2,6,6-tetramethyl piperidine-4-yl)-3-(pyridin-4-yl) guanidine.

In other other specific embodiment, multifunctional nitrogen oxygen derivative of the present invention is the compound of general formula I, and wherein Y is N; X is-(CR₂R₂)_n-, wherein n is 1; R₁Be F, Cl or Br, be connected to the position 6 of pyridine ring; R₂Be H; R₃It is methyl; And A is connected to theposition 2,3,4 or 5 of pyridine ring, that is 2-cyano group-1-(6-fluorine pyridine-2-yl)-3-(1-hydroxyl-2,2,, 6,6-tetramethyl piperidine-4-yl) guanidine, 2-cyano group-1-(6-chloropyridine-2-yl)-3-(1-hydroxyl-2,2,6,6-tetramethyl piperidine-4-yl) guanidine or 2-cyano group-1-(6-bromopyridine-2-yl)-3-(1-hydroxyl-2,2,6,6-tetramethyl piperidine-4-yl) the oxygen base of guanidine (is respectively compound 11_a-11_c); 2-cyano group-1-(6-fluorine pyridin-3-yl)-3-(1-hydroxyl-2,2,6,6-tetramethyl piperidine-4-yl) guanidine, 2-cyano group-1-(6-chloropyridine-3-yl)-3-(1-hydroxyl-2,2,6,6-tetramethyl piperidine-4-yl) guanidine or 2-cyano group-1-(6-bromopyridine-3-yl)-3-(1-hydroxyl-2,2,6,6-tetramethyl piperidine-4-yl) the oxygen base of guanidine (is respectively compound 12_a-12_c); 2-cyano group-1-(6-fluorine pyridin-4-yl)-3-(1-hydroxyl-2,2,6,6-tetramethyl piperidine-4-yl) guanidine, 2-cyano group-1-(6-chloropyridine-4-yl)-3-(1-hydroxyl-2,2,6,6-tetramethyl piperidine-4-yl) guanidine or 2-cyano group-1-(6-bromopyridine-4-yl)-3-(1-hydroxyl-2,2,6,6-tetramethyl piperidine-4-yl) the oxygen base of guanidine (is respectively compound 13_a-13_c); Or 2-cyano group-1-(6-fluorine pyridine-5-yl)-3-(1-hydroxyl-2,2,6,6-tetramethyl piperidine-4-yl) guanidine, 2-cyano group-1-(6-chloropyridine-5-yl)-3-(1-hydroxyl-2,2,6,6-tetramethyl piperidine-4-yl) guanidine or 2-cyano group-1-(6-bromopyridine-5-yl)-3-(1-hydroxyl-2,2,6,6-tetramethyl piperidine-4-yl) the oxygen base of guanidine (is respectively compound 14_a-14_c).

In other specific embodiment, multifunctional nitrogen oxygen derivative of the present invention is the compound of general formula I, and wherein Y is N; X is-(CR₂R₂)_n-, wherein n is 2, R₁Do not exist; R₂Be H; R₃It is methyl; And A is connected to theposition 2,3 or 4 of pyridine ring, that is, and and the oxygen base (compound 15) of 2-cyano group-1-(1-hydroxyl-2,2,7,7-tetramethyl-azepan-4-yl)-3-(pyridine-2-yl) guanidine; The oxygen base (compound 16) of 2-cyano group-1-(1-hydroxyl-2,2,7,7-tetramethyl-azepan-4-yl)-3-(pyridin-3-yl) guanidine; Or the oxygen base (compound 17) of 2-cyano group-1-(1-hydroxyl-2,2,7,7-tetramethyl-azepan-4-yl)-3-(pyridin-4-yl) guanidine.

Table 4: this paper is designated the multifunctional nitrogen oxygen derivative of compound 1-21

* wherein the F atom is had the identifier number identical with configuration " b " or " c " respectively by Cl or the alternative compound of Br.

In other specific embodiment, multifunctional nitrogen oxygen derivative of the present invention is the compound of general formula I, and wherein Y is N; X is-(CR₂R₂)_n-, wherein n is 2; R₁Be F, Cl or Br, be connected to the position 6 of pyridine ring; R₂Be H; R₃It is methyl; And A is connected to the position 2,3,4 or 5 of pyridine ring, that is 2-cyano group-1-(6-fluorine pyridine-2-yl)-3-(1-hydroxyl-2,2,, 7,7-tetramethyl-azepan-4-yl) guanidine, 2-cyano group-1-(6-chloropyridine-2-yl)-3-(1-hydroxyl-2,2,7,7-tetramethyl-azepan-4-yl) guanidine or 2-cyano group-1-(6-bromopyridine-2-yl)-3-(1-hydroxyl-2,2,7,7-tetramethyl-azepan-4-yl) the oxygen base of guanidine (is respectively compound 18_a-18_c); 2-cyano group-1-(6-fluorine pyridin-3-yl)-3-(1-hydroxyl-2,2,7,7-tetramethyl-azepan-4-yl) guanidine, 2-cyano group-1-(6-chloropyridine-3-yl)-3-(1-hydroxyl-2,2,7,7-tetramethyl-azepan-4-yl) guanidine or 2-cyano group-1-(6-bromopyridine-3-yl)-3-(1-hydroxyl-2,2,7,7-tetramethyl-azepan-4-yl) the oxygen base of guanidine (is respectively compound 19_a-19_c); 2-cyano group-1-(6-fluorine pyridin-4-yl)-3-(1-hydroxyl-2,2,7,7-tetramethyl-azepan-4-yl) guanidine, 2-cyano group-1-(6-chloropyridine-4-yl)-3-(1-hydroxyl-2,2,7,7-tetramethyl-azepan-4-yl) guanidine or 2-cyano group-1-(6-bromopyridine-4-yl)-3-(1-hydroxyl-2,2,7,7-tetramethyl-azepan-4-yl) the oxygen base of guanidine (is respectively compound 20_a-20_c); Or 2-cyano group-1-(6-fluorine pyridine-5-yl)-3-(l-hydroxyl-2,2,7,7-tetramethyl-azepan-4-yl) guanidine, 2-cyano group-1-(6-chloropyridine-5-yl)-3-(l-hydroxyl-2,2,7,7-tetramethyl-azepan-4-yl) guanidine or 2-cyano group-1-(6-bromopyridine-5-yl)-3-(l-hydroxyl-2,2,7,7-tetramethyl-azepan-4-yl) the oxygen base of guanidine (is respectively compound 21_a-21_c).

In some specific embodiment, multifunctional nitrogen oxygen derivative of the present invention is the compound of general formula I, and wherein Y is CH; A is connected to the optional position of phenyl ring; R₁Do not exist or be 1 to 5 substituting group, each substituting group is halogen independently; X does not exist or is-(CR₂R₂)_n-, wherein n is 1 or 2; Each R₂Be H; Each R₃Be (C independently₁-C₄) alkyl, preferred (C₁-C₂) alkyl, more preferably methyl; R₄Be H; And R₅Be-CN.In some more particular embodiment, R₁Be the unique substituting group that is connected to arbitrarily effective carbon atom in the phenyl ring, that is, and at the halogen that is connected to phenyl ring with respect to the position adjacent, alternate or relative with group A.In other more particular embodiment, R₁Represent 2 substituting groups, each substituting group is connected to arbitrarily effective carbon atom in the phenyl ring independently,, is connected to two halogens of phenyl ring in relative to each other adjacent, alternate or relative position that is.(each compound has three kinds of configurations to this concrete compounds described in the specification sheets among compound 23-25,33-35 and the 37-39 with the Arabic alphabet 22-39 of runic sign at this paper, be designated a-c), wherein their complete chemical structure is described in following table 5.

In a specific embodiment, multifunctional nitrogen oxygen derivative of the present invention is the compound of general formula I, and wherein Y is CH; X does not exist; R₁Do not exist; R₂Be H; And R₃Be methyl, that is, and the oxygen base (compound 22) of 2-cyano group-1-(1-hydroxyl-2,2,5,5-tetramethylpyrrolidi-e-3-yl)-3-guanidines.

In other specific embodiment, multifunctional nitrogen oxygen derivative of the present invention is the compound of general formula I, and wherein Y is CH; X does not exist; R₂Be H; R₃It is methyl; And R₁Be F, Cl or Br, be connected to phenyl ring in the position adjacent, alternate or relative with respect to A, namely, 2-cyano group-1-(2-fluorophenyl)-3-(l-hydroxyl-2,2,5,5-tetramethylpyrrolidi-e-3-yl) guanidine, 2-cyano group-1-(2-chloro-phenyl-)-3-(l-hydroxyl-2,2,5,5-tetramethylpyrrolidi-e-3-yl) guanidine or 2-cyano group-1-(2-bromophenyl)-3-(l-hydroxyl-2,2,5,5-tetramethylpyrrolidi-e-3-yl) the oxygen base of guanidine (is respectively compound 23_a-23_c); 2-cyano group-1-(3-fluorophenyl)-3-(1-hydroxyl-2,2,5,5-tetramethylpyrrolidi-e-3-yl) guanidine, 2-cyano group-1-(3-chloro-phenyl-)-3-(1-hydroxyl-2,2,5,5-tetramethylpyrrolidi-e-3-yl) guanidine or 2-cyano group-1-(3-bromophenyl)-3-(1-hydroxyl-2,2,5,5-tetramethylpyrrolidi-e-3-yl) the oxygen base of guanidine (is respectively compound 24_a-24_c); Or 2-cyano group-1-(4-fluorophenyl)-3-(1-hydroxyl-2,2,5,5-tetramethylpyrrolidi-e-3-yl) guanidine, 2-cyano group-1-(4-chloro-phenyl-)-3-(1-hydroxyl-2,2,5,5-tetramethylpyrrolidi-e-3-yl) guanidine or 2-cyano group-1-(4-bromophenyl)-3-(1-hydroxyl-2,2,5,5-tetramethylpyrrolidi-e-3-yl) the oxygen base of guanidine (is respectively compound 25_a-25_c).

In other specific embodiment, multifunctional nitrogen oxygen derivative of the present invention is the compound of general formula I, and wherein Y is CH; X does not exist; R₂Be H; R₃It is methyl; And R₁Represent 2 substituting groups, each substituting group is F, Cl or Br independently, is connected to phenyl ring in the position adjacent, alternate or relative with respect to A.In these concrete embodiments, multifunctional nitrogen oxygen derivative of the present invention is the compound of general formula I, wherein R₁Represent 2 substituting groups, each substituting group is Cl, is connected to phenyl ring in and position adjacent adjacent with respect to A, that is, and and the oxygen base (compound 26) of 2-cyano group-1-(2,6-dichlorophenyl)-3-(1-hydroxyl-2,2,5,5-tetramethylpyrrolidi-e-3-yl) guanidine; Be connected to phenyl ring in the position adjacent and alternate with respect to A, namely, 2-cyano group-1-(2,5-dichlorophenyl)-3-(1-hydroxyl-2,2,5,5-tetramethylpyrrolidi-e-3-yl) guanidine or 2-cyano group-1-(2,3-dichlorophenyl)-3-(1-hydroxyl-2,2,5,5-tetramethylpyrrolidi-e-3-yl) the oxygen base of guanidine (being respectively compound 27 and 28); Be connected to phenyl ring in the position adjacent with relative with respect to A, that is, and the oxygen base (compound 29) of 2-cyano group-1-(2,4 dichloro benzene base)-3-(1-hydroxyl-2,2,5,5-tetramethylpyrrolidi-e-3-yl) guanidine; Be connected to phenyl ring in the position alternate and alternate with respect to A, that is, and the oxygen base (compound 30) of 2-cyano group-1-(3,5-dichlorophenyl)-3-(1-hydroxyl-2,2,5,5-tetramethylpyrrolidi-e-3-yl) guanidine; Or be connected to phenyl ring in the position alternate with relative with respect to A, that is, and the oxygen base (compound 31) of 2-cyano group-1-(3,4-dichlorophenyl)-3-(1-hydroxyl-2,2,5,5-tetramethylpyrrolidi-e-3-yl) guanidine.

In another specific embodiment, multifunctional nitrogen oxygen derivative of the present invention is the compound of general formula I, and wherein Y is CH; X is-(CR₂R₂)_n-, wherein n is 1; R₁Do not exist; R₂Be H; And R₃Be methyl, that is, and the oxygen base (compound 32) of 2-cyano group-1-(1-hydroxyl-2,2,6,6-tetramethyl piperidine-4-yl)-3-guanidines.

In other specific embodiment, multifunctional nitrogen oxygen derivative of the present invention is the compound of general formula I, and wherein Y is CH; X is-(CR₂R₂)_n-, wherein n is 1; R₂Be H; R₃It is methyl; And R₁Be F, Cl or Br, be connected to phenyl ring in the position adjacent, alternate or relative with respect to A, namely, 2-cyano group-1-(2-fluorophenyl)-3-(1-hydroxyl-2,2,6,6-tetramethyl piperidine-4-yl) guanidine, 2-cyano group-1-(2-chloro-phenyl-)-3-(1-hydroxyl-2,2,6,6-tetramethyl piperidine-4-yl) guanidine or 2-cyano group-1-(2-bromophenyl)-3-(1-hydroxyl-2,2,6,6-tetramethyl piperidine-4-yl) the oxygen base of guanidine (is respectively compound 33_A-c); 2-cyano group-1-(3-fluorophenyl)-3-(l-hydroxyl-2,2,6,6-tetramethyl piperidine-4-yl) guanidine, 2-cyano group-1-(3-chloro-phenyl-)-3-(l-hydroxyl-2,2,6,6-tetramethyl piperidine-4-yl) guanidine or 2-cyano group-1-(3-bromophenyl)-3-(l-hydroxyl-2,2,6,6-tetramethyl piperidine-4-yl) the oxygen base of guanidine (is respectively compound 34_A-c); Or 2-cyano group-1-(4-fluorophenyl)-3-(1-hydroxyl-2,2,6,6-tetramethyl piperidine-4-yl) guanidine, 2-cyano group-1-(4-chloro-phenyl-)-3-(1-hydroxyl-2,2,6,6-tetramethyl piperidine-4-yl) guanidine or 2-cyano group-1-(4-bromophenyl)-3-(1-hydroxyl-2,2,6,6-tetramethyl piperidine-4-yl) the oxygen base of guanidine (is respectively compound 35_A-c).

In other specific embodiment, multifunctional nitrogen oxygen derivative of the present invention is the compound of general formula I, and wherein Y is CH; X is-(CR₂R₂)_n-, wherein n is 1; R₂Be H; R₃It is methyl; And R₁Represent 2 substituting groups, each substituting group is F, Cl or Br independently, is connected to phenyl ring in the position adjacent, alternate or relative with respect to A.

In another specific embodiment, multifunctional nitrogen oxygen derivative of the present invention is the compound of general formula I, and wherein Y is CH; X is-(CR₂R₂)_n-, wherein n is 2; R₁Do not exist; R₂Be H; And R₃Be methyl, that is, and the oxygen base (compound 36) of 2-cyano group-1-(1-hydroxyl-2,2,7,7-tetramethyl-azepan-4-yl)-3-guanidines.

In other specific embodiment, multifunctional nitrogen oxygen derivative of the present invention is the compound of general formula I, and wherein Y is CH; X is-(CR₂R₂)_n-, wherein n is 2; R₂Be H; R₃It is methyl; And R₁Be F, Cl or Br, be connected to phenyl ring in the position adjacent, alternate or relative with respect to A, namely, 2-cyano group-1-(2-fluorophenyl)-3-(1-hydroxyl-2,2,7,7-tetramethyl-azepan-4-yl) guanidine, 2-cyano group-1-(2-chloro-phenyl-)-3-(1-hydroxyl-2,2,7,7-tetramethyl-azepan-4-yl) guanidine or 2-cyano group-1-(2-bromophenyl)-3-(1-hydroxyl-2,2,7,7-tetramethyl-azepan-4-yl) the oxygen base of guanidine (is respectively compound 37_A-c); 2-cyano group-1-(3-fluorophenyl)-3-(l-hydroxyl-2,2,7,7-tetramethyl-azepan-4-yl) guanidine, 2-cyano group-1-(3-chloro-phenyl-)-3-(l-hydroxyl-2,2,7,7-tetramethyl-azepan-4-yl) guanidine or 2-cyano group-1-(3-bromophenyl)-3-(l-hydroxyl-2,2,7,7-tetramethyl-azepan-4-yl) the oxygen base of guanidine (is respectively compound 38_A-c); Or 2-cyano group-1-(4-fluorophenyl)-3-(1-hydroxyl-2,2,7,7-tetramethyl-azepan-4-yl) guanidine, 2-cyano group-1-(4-chloro-phenyl-)-3-(1-hydroxyl-2,2,7,7-tetramethyl-azepan-4-yl) guanidine or 2-cyano group-1-(4-bromophenyl)-3-(1-hydroxyl-2,2,7,7-tetramethyl-azepan-4-yl) the oxygen base of guanidine (is respectively compound 39_A-c).

In other specific embodiment, multifunctional nitrogen oxygen derivative of the present invention is the compound of general formula I, and wherein Y is CH; X is-(CR₂R₂)_n-, wherein n is 1; R₂Be H; R₃It is methyl; And R₁Represent two substituting groups, each substituting group is F, Cl or Br independently, is connected to phenyl ring in the position adjacent, alternate or relative with respect to A.

Table 5: this paper is designated the multifunctional nitrogen oxygen derivative of compound 22-39

* wherein the F atom is had respectively and configuration b by Cl or the alternative compound of Br " or " c " identical identifier number.

In some specific embodiment, multifunctional nitrogen oxygen derivative of the present invention is the compound of general formula I, wherein Y be N (→ O); A is connected to theposition 2,3,4,5 or 6 of pyridine ring; R₁Do not exist or be 1 to 4 substituting group, each substituting group is halogen independently; X does not exist or is-(CR₂R₂)_n-, wherein n is 1 or 2; Each R₂Be H; Each R₃Be (C independently₁-C₄) alkyl, preferred (C₁-C₂) alkyl, more preferably methyl; R₄Be H; And R₅Be-CN.In some more particular embodiment, R₁Be the unique substituting group that is connected to arbitrarily effective carbon atom of pyridine oxide ring, that is, be connected to the halogen of pyridine oxide ring in the position adjacent, alternate or relative with respect to group A.In other more particular embodiment, R₁Represent 2 substituting groups, each substituting group is connected to arbitrarily effective carbon atom of pyridine oxide ring independently,, is connected to two halogens of pyridine oxide ring in relative to each other adjacent, alternate or relative position that is.

A plurality of multifunctional nitrogen oxygen derivative of the present invention can be synthetic according to any technology as known in the art or program, for example, and described in following examples part.

Multifunctional nitrogen oxygen derivative of the present invention can have one or more asymmetric centers, and therefore can be used as enantiomer and diastereomer exists, enantiomer namely learn isomer (R, S or racemic modification, wherein certain enantiomer can have 90%, 95%, 99% or higher optical purity).Particularly, those chiral centres can be for example in each carbon atom of the oxygen base of 1-hydroxyl pyrrolidine-3-base, 1-hydroxy piperidine-4-base or 1-hydroxyl azepan-4-base section; Also can be in the arbitrary-NH group of guanidine radicals part or both.Should be appreciated that, the present invention contain all these type of enantiomers, isomer and its mixture with and pharmacy acceptable salt, solvate and prodrug.

Can use any means known in the art to prepare the optical activity form of multifunctional nitrogen oxygen derivative of the present invention, for example, by recrystallization technology racemic form be split; Synthetic by chirality; By extracting with chiral solvent; Or by using chiral stationary phase to carry out chromatographic separation.A limiting examples that is used for the method for acquisition optically active substance is to pass the chiral film transportation, namely, so as to racemic modification is contacted with thin barrier film, the concentration difference differential pressure causes preferentially passing envelope barrier transportation, and owing to only allows the technology of the separation that the non-racemize chirality character of the film that an enantiomer of racemic modification passes through takes place.Also can use the chirality chromatography, comprise simulated moving bed chromatography.The commercially available acquisition of multiple chiral stationary phase.

As mentioned above, find that administeredcompound 2 is beneficial to treatment, prevention and/or processing various diseases, illness or the symptom relevant with oxidative stress or endothelial function disturbance very much.

Shown in embodiment 11, in the rat model of Myocardial Ischemia Reperfusion Injury (MIRI),compound 2 significantly reduces myocardium myeloperoxidase (MPO) and tissue infraction.Specifically, yet compare serious myocyte's necrosis that MIRI induces, oedema and neutrophil infiltration (center), all histologic characteristicses in fact that administeredcompound 2 obviously weakens damage before pouring into again with the sham-operation contrast.And in the pre-shrunk isolated rat vascular circle of norepinephrine system,discovery compound 2 is compared with Pinacidil (pinacidil), is not to be effectively myocardium vessel expander, its ED₅₀Greater than logarithm of Pinacidil, show sarolemma K⁺The loss of-ATP passage activation.

Embodiment 12 has shown that the mouse model of 2 pairs of renal ischaemia-reperfusion injuries of compound further protects.More particularly, again before the perfusion,compound 2 joined stand the CD mouse that kidney base of a fruit bilateral folder closes, obviously weaken blood plasma blood urea nitrogen and creatinine, and the rising of kidney myeloperoxidase (a kind of marker of neutrophil infiltration); And as disclose by Histological research, provide almost completely protection to serious renal tubular necrosis.

Compound 2 finds that also it can be effectively as rescue therapy, shown in embodiment 13 in the mouse model of acute chlorine suction damage except the therapeutic property to the ischemia reperfusion injury model.Shown in concrete, continue to be exposed to behind the chlorine 15 minutes, thecompound 2 that the Balb/c mouse is used reduces rising (level as myocardium myeloperoxidase (MPO) reflects) and the lung tissue that polymorphonuclear leukocyte (PMN) soaks into significantly to be damaged.As further shown,compound 2 weakens injury of lung in the dose-dependently mode, as the histology score institute example by improving.

Embodiment 14 demonstrates with salt solution vehicle group and compares, and 2 pairs of glucose levels of compound do not show any obvious influence.

Therefore, in yet another aspect, the invention provides a kind of pharmaceutical composition, it comprises the multifunctional nitrogen oxygen derivative of general formula I as defined above, or its enantiomer, diastereomer, racemic modification or pharmacy acceptable salt, solvate or prodrug and pharmaceutically acceptable supporting agent.In specific embodiment, pharmaceutical composition of the present invention comprises multifunctional nitrogen oxygen derivative, and it is selected from compound 1-39 or its enantiomer, diastereomer, racemic modification or pharmacy acceptable salt, solvate or prodrug.

Multifunctional nitrogen oxygen derivative of the present invention and composition can several formulations provide, for example, and with pharmaceutically acceptable form and/or with salt or solvate (for example, hydrate) form, and with multiple dosage.Multifunctional nitrogen oxygen derivative of the present invention also can be pharmaceutically acceptable the form of prodrug provide.

As used herein, term " prodrug " but refer to internal metabolism or transform so that the compound of the multifunctional nitrogen oxygen derivative of general formula I as defined above to be provided that this process is called bioactivation.Use the ultimate principle of prodrug normally in order to make absorption, distribution, metabolism and secretion optimizing, wherein usually prodrug is designed to improve the oral bioavailability rate, usually be limiting factor from GI bad absorption wherein, and/or increase medicine to the selectivity of its required target.Limiting examples according to prodrug of the present invention comprises the compound of preparation in the following way, via suitable heteroatoms or connection base, ester, carbamate, carbonic ether or benzyl are added to pyridine ring, phenyl ring or pyridine oxide ring, but or are added to dicyanodiamide part in the multifunctional nitrogen oxygen derivative of general formula I internal metabolism to be provided or to transform to obtain the respective compound of described multifunctional nitrogen oxygen derivative.Described modification example is Horino etc. for example as seen, Novel potassium channel opener prodrugs with a slow onset and prolonged duration of action, Chem.Pharm.Bull (Tokyo), 2000,48 (4), 490-495; With Uematsu etc., Pharmacokinetics and safety of a novel, long-acting, prodrug-type potassium channel opener, Y-27152, healthy volunteers, J.Clin.Pharmacol., 1996,36 (5), 439-451.

In one embodiment, pharmaceutical composition of the present invention comprises the nontoxic pharmacy acceptable salt of the multifunctional nitrogen oxygen derivative of general formula I.Suitable pharmacy acceptable salt comprises acid salt, such as but not limited to, mesylate; Maleate, fumarate, tartrate, hydrochloride, hydrobromate, esilate; Tosilate, benzoate, acetate, phosphoric acid salt, vitriol, Citrate trianion, carbonate and succinate.Other pharmacy acceptable salt comprises ammonium (NH₄⁺) or derived from formula R₄N⁺The organic cations salt of amine, wherein each R is independently selected from H, C₁-C₂₂, preferred C₁-C₆Alkyl, for example methyl, ethyl, propyl group, sec.-propyl, normal-butyl, sec-butyl, isobutyl-, the tertiary butyl, n-pentyl, 2,2-dimethyl propyl, n-hexyl etc., phenyl or heteroaryl, for example pyridyl, imidazolyl, pyrimidyl etc., or the nitrogen-atoms that connects with them of two R forms and randomly comprises the heteroatomic 3-7 unit ring that another is selected from N, S and O, for example tetramethyleneimine, piperidines and morpholine.And when multifunctional nitrogen oxygen derivative of the present invention carried acidic moiety, its suitable pharmacy acceptable salt can comprise metal-salt, for example, and an alkali metal salt, for example, lithium salts, sodium salt or sylvite, and alkaline earth salt, for example, calcium salt or magnesium salts.

Other pharmacy acceptable salt comprises the salt of cation lipid or cation lipid mixture.Cation lipid is mixing with neutral lipid as before the delivery agents usually.Neutral lipid includes but not limited to, Yelkin TTS; Phosphatidylethanolamine; Diacyl phosphatidylethanolamine, for example dioleoyl phosphatidylethanolamine, two palmitoyl phosphatidylethanolamines, palmitoyl oleoyl phosphatidylethanolamine and distearyl acyl group phosphatidylethanolamine; Phosphatidylcholine; Diacyl phosphatidyl choline, for example, dioleyl phosphatidyl choline, two palmitoyl phosphatidylcholines, palmitoyl oleoyl phosphatidylcholine and DSPC; Phosphatidyl glycerol; The diacyl phosphatidyl glycerol, for example, dioleoyl phosphatidyl glycerol, DPPG and DSPG; Phosphatidylserine; The diacyl phosphatidylserine, for example, dioleoyl-or DPPS; And diphosphatidylglycerol; Fatty acid ester; Glyceryl ester; Sphingophospholipid; Val; Cerebroside; Ceramide; With and composition thereof.Neutral lipid also comprises cholesterol and other 3 β hydroxyl-sterol.

The cation lipid examples for compounds includes but not limited to,(Life Technologies, Burlington, Ontario) (cation lipid N-[l-(2,3-, two oleyl oxygen bases) propyl group]-N, N, 1:1 (w/w) preparation of N-trimethyl ammonium chloride and dioleoyl phosphatidylethanolamine); Lipofectamine^TM(Life Technologies; Burlington; Ontario) (polycationic lipid 2; 3-two oleyl oxygen base-N-[2 (spermine-formamido-) ethyls]-N; 3:1 (w/w) preparation of N-dimethyl-1-propylamine-trifluoroacetate and dioleoyl phosphatidylethanolamine); Lipofectamine Plus (Life Technologies; Burlington; Ontario) (Lipofectamine and Plus reagent); Lipofectamine2000 (LifeTechnologies; Burlington; Ontario) (cation lipid); Effectene (Qiagen; Mississauga; Ontario) (non-liposome lipid preparation); Metafectene (Biontex; Munich; Germany) (polycationic lipid); Eu-fectins (Promega Biosciences; San Luis Obispo, Calif.) (ethanol cation lipid 1-12:C₅₂H₁₀₆N₆O₄4CF₃CO₂H, C₈₈H₁₇₈N₈O₄S₂4CF₃CO₂H, C₄₀H₈₄NO₃PCF₃CO₂H, C₅₀H_L03N₇O₃4CF₃CO₂H, C₅₅H₁₁₆N₈O₂6CF₃CO₂H, C₄₉H₁₀₂N₆O₃4CF₃CO₂H, C₄₄H₈₉N₅O₃2CF₃CO₂H, C₁₀₀H₂₀₆N₁₂O₄S₂8CF₃CO₂H, C₁₆₂H₃₃₀N₂₂O₉13CF₃CO₂H, C₄₃H₈₈N₄O₂2CF₃CO₂H, C₄₃H₈₈N₄O₃2CF₃CO₂H, C₄₁H₇₈NO₈P); Cytofectene (Bio-Rad, Hercules, Calif.) (mixture of cation lipid and neutral lipid),

(Gene Therapy Systems, San Diego, Calif.) (preparation of neutral lipid (Dope) and cation lipid) and FuGENE6 (Roche Molecular Biochemicals, Indianapolis, Ind.) (based on the polycomponent lipid of non-liposome reagent).

Pharmacy acceptable salt of the present invention can form by traditional method, for example, by making promoting agent (namely, multifunctional nitrogen oxygen derivative of the present invention) free alkali form and the suitable acid of one or more equivalents are in the insoluble solvent of salt or vehicle, or reaction in the solvent (for example water) that but vacuum removes or lyophilize removes, or by exchanging negatively charged ion/positively charged ion at suitable ion exchange resin.

In one embodiment, pharmaceutical composition of the present invention is mixed with nano particle.

Pharmaceutical composition provided by the invention rule technology preparation usually, for example, as Remington:The Science and Practice of Pharmacy, the 19th edition, described in 1995.Composition can (for example) by promoting agent (for example, multifunctional nitrogen oxygen derivative of the present invention) and liquid carrier, fine-grained solids supporting agent or both evenly and are fully associated, then, in case of necessity, the required preparation of the moulding one-tenth of product is prepared.Composition can be solid, semisolid or liquid form and can comprise pharmaceutically acceptable filler, supporting agent, thinner or adjuvant and other inert fraction and vehicle in addition.Composition can be prepared to be used for any suitable route of administration, for example, oral, intranasal stomach, intranasal intestines, per os stomach, parenteral (for example, intramuscular, subcutaneous, intraperitoneal, intravenously, intra-arterial or subcutaneous injection or implant), irritate stomach, through cheek, intranasal, hypogloeeis or topical application and be used for sucking.Dosage will depend on patient's states, and will think an amount of by the doctor and determine.

Pharmaceutical composition of the present invention can be to be suitable for oral form, for example, but tablet, lozenge, lozenge, water-based or oily suspensions dispersed powders or particle, emulsion, hard or soft capsule or syrup or elixir.Can and can comprise one or more in addition according to any means preparation for the manufacture of pharmaceutical composition known in the art for oral composition and be selected from following medicament: sweeting agent, seasonings, tinting material and sanitas are to obtain pharmaceutically attractive in appearance and good to eat preparation.Tablet contains activeconstituents and is suitable for making the mixture of the nontoxic pharmaceutically acceptable vehicle of tablet.These vehicle can be for example inert diluent, for example calcium carbonate, yellow soda ash, lactose, calcium phosphate or sodium phosphate; Granulating agent and disintegrating agent, for example, W-Gum or alginic acid; Tamanori, for example, starch, gelatin or gum arabic; And lubricant, for example, Magnesium Stearate, stearic acid or talcum.Tablet can not coat or utilize known technology to be coated with to delay disintegration and the absorption in gi tract, and and then is provided at continuous action in the long period section.For example, can adopt the time-delay material, for example glyceryl monostearate or distearin.They also can use U.S. Patent number 4,256, and 108,4,166,452 and 4,265, the technology described in 874 is coated with the osmotic therapeutic tablets that forms controlled release.Pharmaceutical composition of the present invention also can be the form of O/w emulsion.

Pharmaceutical composition of the present invention can be the form of sterile injectable water-based or oleagenous suspension, and it can use suitable dispersion agent, wetting agent or suspension agent to prepare according to known technology.Sterile injectable preparation also can be sterile injectable solution or the suspension in nontoxic parenteral acceptable diluent or solvent.Adoptable acceptable vehicle and solvent include but not limited to, water, Ringer's solution (Ringer's solution) and isotonic sodium chlorrde solution.

Pharmaceutical composition of the present invention can above suitable form, for example, tablet (for example, matrix tablet), wherein the release of soluble active agent by making promoting agent and diffuse through and dissolving the expand gel of back formation of hydrophilic polymer that liquid (external) or gastrointestinal fluid (body in) contact and control.The multiple polymers that can form this gel has been described, for example, cellulosic derivative, especially ether of cellulose, for example, hydroxypropylcellulose, Walocel MT 20.000PV, methylcellulose gum or methylhydroxypropylcellulose and show quite full-bodied those ethers in the ether of these different commercial grades.

Pharmaceutical composition of the present invention can comprise preparation for the promoting agent with the microcapsule formulations controlled release, and wherein the small droplets of promoting agent is surrounded to form several microns to several millimeters particles in the scope by dressing or film, or adopts the controlled release matrix form.

The preparation of another kind of expection is based on the storehouse system of Biodegradable polymeric, wherein when polymer degradation, discharges promoting agent lentamente.A modal class biodegradable polymer is the polyester by the hydrolytically unstable of the combined preparation of lactic acid, oxyacetic acid or these two kinds of molecules.By the polymkeric substance of these independent monomers preparations comprise poly-(D, L-rac-Lactide) (PLA), poly-(glycollide) (PGA) and poly-(D, the L-rac-Lactide-glycollide) multipolymer (PLG) of multipolymer.

According to pharmaceutical composition of the present invention, when preparation is used for sucking, can utilize any suitable device known in the art to use, for example metered-dose inhaler, liquid dispenser, Diskus, atomizer, hot vaporizer, electrohydrodynamic fog machine (electrohydrodynamic aerosolizer) etc.

Multifunctional nitrogen oxygen derivative of the present invention and pharmaceutical composition is used for the treatment of, prevention and/or processing and high-caliber reactive oxygen species (ROS) (that is oxidative stress) or relevant disease, illness or the symptom of endothelial function disturbance.

In one embodiment, relevant with oxidative stress or endothelial function disturbance described disease, illness or symptom are disease, illness or the symptom relevant with ischemia reperfusion injury.The unrestricted example of this type of disease comprises septicemia, septic shock, apoplexy, cataract forms, glaucoma, ground pattern atrophy (geographic atrophy), macular degeneration, stenocardia, hemorrhagic shock, the circulation shock that superantigen is induced, renal reperfusion injury, the ephrosis that contrast medium is induced, retinopathy of prematurity, necrotizing enterocolitis, congenital alveolar dysplasia, ischemia-reperfusion lung injury (for example, after transplanting), the complication of IL-2 biotherapy, myocardial infarction, the complication of cardiopulmonary bypass surgery, the limbs reperfusion injury, the erective dysfunction that the prostate excision postoperative is relevant, (comprise carotid endarterectomy with vascular surgery, aortic aneurysm is repaired, peripheral arterial embolectomy and thrombectomy) relevant complication of perfusion again, crush injury, the interval syndromes, organ is preserved, head trauma and Spinal injury.

In another embodiment, described disease, illness or the symptom relevant with oxidative stress or endothelial function disturbance are neurodegenerative diseases, such as but not limited to, Parkinson's disease (Parkinson's disease), Alzheimer's (Alzheimer's disease) and amyotrophic lateral sclerosis.

In another embodiment, relevant with oxidative stress or endothelial function disturbance described disease, illness or symptom are inflammatory or immunological disease.In some specific embodiment, described inflammatory or immunological disease are selected from septicemia, uveitis, rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, the inflammation joint, eczema, inflammatory dermatosis, inflammatory eye disease, conjunctivitis, the tissue necrosis that is caused by inflammation, tissue rejection after the transplantation, graft versus host disease (GVH disease), Crohn's disease (Crohn'sdisease) and ulcerative colitis, airway inflammation, asthma, bronchitis, systemic lupus erythematous, multiple sclerosis, glaucoma, the injury of lung that smoking is induced, pulmonary fibrosis, pancreatitis, myocardosis (comprising the myocardosis that chemotherapy is induced), the complication of IL-2 biotherapy, diabetes, diabetic complication (comprising diabetic retinopathy), peripheral neuropathy, acute macular degeneration, skin ulcer, ephrosis, pneumonia, mucositis, adult respiratory distress syndrome, cigarette sucks or skin burn.In other specific embodiment, described inflammatory diseases is by the inflammatory diseases that sucks toxic agent or the caused lung of stimulator (for example chlorine, phosgene and cigarette).

In another embodiment, described disease, illness or the symptom relevant with oxidative stress or endothelial function disturbance be cancer or with the chemotherapy of cancer or radiation therapy relevant symptom.

Therefore, in yet another aspect, the invention provides the multifunctional nitrogen oxygen derivative of general formula I as defined above, or its enantiomer, diastereomer, racemic modification or pharmacy acceptable salt, solvate or prodrug, it is used for the treatment of disease, illness or the symptom relevant with oxidative stress or endothelial function disturbance.

In yet another aspect, the invention provides the method that is used for the treatment of disease, illness or the symptom relevant with oxidative stress or endothelial function disturbance, described method comprises the multifunctional nitrogen oxygen derivative to the general formula I as defined above of the individual administering therapeutic significant quantity that needs are arranged, or its enantiomer, diastereomer, racemic modification or pharmacy acceptable salt, solvate or prodrug.

To set forth the present invention by following non-limiting example now.

Embodiment

Synthesizing ofembodiment 1.compounds 2

Asscheme 1 general introduction, with the different sulphur cyanato of 3-pyridine (1.735g) and 3-amino-2,2,5, the 5-tetramethylpyrrolidi-e-mixture of nitrogen oxygen (2.0g) in methylene dichloride (30ml) at room temperature stirred 8 hours.Thin-layer chromatography (TLC) demonstrates some unreacted parent materials.Reaction mixture is at room temperature stirred spend the night, concentrate by Rotary Evaporators (rotavap) then.The resistates that obtains (l-(pyridin-3-yl)-3-(2,2,5,5-tetramethylpyrrolidi-e-nitrogen oxygen-3-yl) thiocarbamide) (3.730g) is used for further reacting.

Make l-(pyridin-3-yl)-3-(2,2,5,5-tetramethylpyrrolidi-e-nitrogen oxygen-3-yl) thiocarbamide (3.6g), cyanamide (5.125g), 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (EDCI) (2.805g) and the mixture of triethylamine (4.928g) in acetonitrile (50ml) at room temperature stir 24 hours, and mixture was refluxed 4 hours down at 80 ℃.Reaction mixture is concentrated at Rotary Evaporators, and use methyl alcohol-methylene dichloride (5-10%) to carry out purifying at silicagel column to obtain 2-cyano group-1-(1-hydroxyl-2,2,5,5-tetramethylpyrrolidi-e-3-yl)-and the oxygen base of 3-(pyridin-3-yl) guanidine, 2 (3.050g).MS(CI+)m/z301.17(M+l,302.18)。

Scheme 1: for the synthesis of nitrogen oxygen derivative (compound 2,5 for example_b, 25_A-c, 29 and 35_A-c) general procedure

Synthesizing ofembodiment 2.compounds 3

Theoxygen base 3 of 2-cyano group-1-(1-hydroxyl-2,2,5,5-tetramethylpyrrolidi-e-3-yl)-3-(pyridin-4-yl) guanidine synthetic from by 4-different sulphur cyanato pyridine and 3-amino-2,2,5,5-tetramethylpyrrolidi-e-1 nitrogen oxygen prepared in reaction thiocarbamide begins.Then, withembodiment 1 described identical condition under, l-(pyridin-4-yl)-3-(2,2,5, the 5-tetramethylpyrrolidi-e-nitrogen oxygen-3-yl) thiocarbamide and cyanamide, EDCI and the diisopropylethylamine that obtain are reacted in DMF, obtain required dicyanodiamide product.

Embodiment 3.compounds 5_bSynthetic

Asscheme 1 general introduction, make (3-amino-2,2,5,5-tetramethylpyrrolidi-e-1-yl) (1.580g, 0.01mol) (1.706g, 0.01mol) mixture in methylene dichloride (20ml) at room temperature stirred 24 hours oxyradical with 6-chloro-3-pyridyl lsothiocyanates.Reaction mixture is concentrated atRotary Evaporators.Use 5% methyl alcohol-methylene dichloride, make the resistates purifying on silicagel column that obtains after concentrating, obtain being yellow oil (3-{[(6-chloropyridine-3-yl) carboxamide sulfonyl] amino }-2,2,5,5-tetramethylpyrrolidi-e-l-yl) oxyradical (3.130g).

Make (3-{[(6-chloropyridine-3-yl) carboxamide sulfonyl] amino }-2; 2; 5; 5-tetramethylpyrrolidi-e-l-yl) oxyradical (2.825g; 0.0086mol), cyanamide (3.612g; 0.086mol), EDCI (2.465g, 0.0129mol) and triethylamine (4.81ml, 0.034mol) mixture in acetonitrile (40ml) refluxed 2 days down at 80 ℃.Reaction mixture is concentrated, and use 5% methyl alcohol-methylene dichloride, make resistates purifying on silicagel column, obtain the oxygen base of faint yellow solid 2-cyano group-1-(6-chloropyridine-3-yl)-3-(l-hydroxyl-2,2,5,5-tetramethylpyrrolidi-e-3-yl) guanidine, 5_b(1.8g).MS(ES⁺)m/z335.14(M+l,336.2)。

Embodiment 4. compounds 25_aSynthetic

Asscheme 1 general introduction, make (3-amino-2,2,5,5-tetramethylpyrrolidi-e-1-yl) (0.532g, 0.0033mol) (0.408ml, 0.0033mol) mixture in methylene dichloride (20ml) at room temperature stirred 3 hours oxyradical with 4-fluorophenyl lsothiocyanates.Reaction mixture is concentrated at Rotary Evaporators, and the resistates that obtains after concentrating is suspended in the hexane.Remove liquid, and make solid dry under vacuum, obtain yellow solid { 2,2,5,5-tetramethyl--3-[(4-fluorophenyl-1-base carboxamide sulfonyl) amino] tetramethyleneimine-1-yl } oxyradical.

Make obtain { 2; 2; 5; 5-tetramethyl--3-[(4-fluorophenyl-1-base carboxamide sulfonyl) amino] tetramethyleneimine-1-yl } oxyradical and cyanamide (1.385g; 0.033mol), EDCI (0.945gm; 0.0049mol) and triethylamine (1.850ml, 0.012mol) merging in acetonitrile (25ml), and under 80 ℃, stirred 24 hours.Reaction mixture is concentrated, and dilute resistates with ethyl acetate and water (each 25ml).Collected organic layer, and concentrated at Rotary Evaporators.Then, use 40-50% ethyl acetate-hexane, make crude product purifying on silicagel column, obtain the oxygen base of 2-cyano group-l-(4-fluorophenyl)-3-(l-hydroxyl-2,2,5,5-tetramethylpyrrolidi-e-3-yl) guanidine, 25_a(0.355gm).MS(ES⁺)m/z318.17(M+l,319.34)。

Embodiment 5. compounds 25_bSynthetic

Asscheme 1 general introduction, make (3-amino-2,2,5,5-tetramethylpyrrolidi-e-1-yl) (0.500g, 0.0031mol) (0.538g, 0.0031mol) mixture in methylene dichloride (25ml) at room temperature stirred 6 hours oxyradical with 4-chloro-phenyl-lsothiocyanates.Reaction mixture is concentrated at Rotary Evaporators, and the resistates that obtains after concentrating is suspended in the hexane.Remove liquid, and make solid dry under vacuum, obtain yellow solid { 2,2,5,5-tetramethyl--3-[(4-chloro-phenyl--l-base carboxamide sulfonyl) amino] tetramethyleneimine-l-yl } oxyradical.

Make obtain { 2; 2; 5; 5-tetramethyl--3-[(4-chloro-phenyl--l-base carboxamide sulfonyl) amino] tetramethyleneimine-l-yl } oxyradical and cyanamide (1.3g; 0.031mol), EDCI (0.710g; 0.0037mol) and triethylamine (1.250g, 0.012mol) merging in acetonitrile (30ml), and under 80 ℃, stirred 24 hours.Reaction mixture is concentrated, and dilute resistates with ethyl acetate and water (each 25ml).Collected organic layer, and concentrated at Rotary Evaporators.Then, use 40% ethyl acetate-hexane, make crude product purifying on silicagel column, obtain the oxygen base of 2-cyano group-l-(4-chloro-phenyl-)-3-(l-hydroxyl-2,2,5,5-tetramethylpyrrolidi-e-3-yl) guanidine, 25_b(0.175g).MS(ES⁺)m/z334.13(M+l,335.25)。

Embodiment 6. compounds 25_cSynthetic

Asscheme 1 general introduction, make (3-amino-2,2,5,5-tetramethylpyrrolidi-e-1-yl) (0.450mg, 0.0028mol) (0.615g, 0.0028mol) mixture in methylene dichloride (30ml) at room temperature stirred 4 hours oxyradical with 4-bromophenyl lsothiocyanates.Reaction mixture is concentrated at Rotary Evaporators, and the resistates that obtains after concentrating is suspended in the hexane.Remove liquid, and make solid dry under vacuum, obtain yellow solid { 2,2,5,5-tetramethyl--3-[(4-bromophenyl-l-base carboxamide sulfonyl) amino] tetramethyleneimine-l-yl } oxyradical.

Make obtain { 2; 2; 5,5-tetramethyl--3-[(4-bromophenyl-l-base carboxamide sulfonyl) amino] tetramethyleneimine-l-yl } oxyradical merges in acetonitrile (25ml) with cyanamide (0.028mol), EDCI (0.0042mol) and triethylamine (0.011mol), and 70 ℃ times stirrings 24 hours.Reaction mixture is concentrated, and dilute resistates with ethyl acetate and water (each 25ml).Collected organic layer, and concentrated at Rotary Evaporators.Then, use 40-100% ethyl acetate-hexane, make crude product purifying on silicagel column, obtain the oxygen base of 2-cyano group-l-(4-bromophenyl)-3-(l-hydroxyl-2,2,5,5-tetramethylpyrrolidi-e-3-yl) guanidine, 25_c(0.280gm).MS(ES⁺)m/z378.10(M+l,379.22)。

Synthesizing of embodiment 7. compounds 29

Asscheme 1 general introduction, (0.500g 0.0031mol) at room temperature stirred 6 hours with the mixture of 2,4 dichloro benzene base lsothiocyanates (0.0034mol) in methylene dichloride (25ml) to make (3-amino-2,2,5,5-tetramethylpyrrolidi-e-1-yl) oxyradical.Reaction mixture is concentrated at Rotary Evaporators, and the resistates that obtains after concentrating is suspended in the hexane.Remove liquid, and make solid dry under vacuum, obtain yellow solid { 2,2,5,5-tetramethyl--3-[(2,4-dichlorophenyl-1-base carboxamide sulfonyl) amino] tetramethyleneimine-1-yl } oxyradical.

Make obtain { 2; 2; 5; 5-tetramethyl--3-[(2; 4-dichlorophenyl-1-base carboxamide sulfonyl) amino] tetramethyleneimine-1-yl oxyradical and cyanamide (1.3g, 0.031mol), EDCI (0.710g, 0.0037mol) and triethylamine (1.250g; 0.012mol) in acetonitrile (30ml), merge, and stirred 24 hours down at 80 ℃.Reaction mixture is concentrated, and dilute resistates with ethyl acetate and water (each 25ml).Collected organic layer, and concentrated at Rotary Evaporators.Then, use 5% methyl alcohol-methylene dichloride, make crude product purifying on silicagel column, obtain the oxygen base of 2-cyano group-1-(2,4 dichloro benzene base)-3-(1-hydroxyl-2,2,5,5-tetramethylpyrrolidi-e-3-yl) guanidine, 29 (0.705gm).MS(ES⁺)m/z368.06(M+l,379.23)。

Embodiment 8. compounds 35_aSynthetic

Asscheme 1 general introduction, make (4-amino-2,2,6,6-tetramethyl piperidine-1-yl) oxyradical (0.500g, 0.0029mol) and the mixture of 4-fluorophenyl lsothiocyanates (0.0029mol) in methylene dichloride (20ml) at room temperature stir and spend the night.Reaction mixture is concentrated at Rotary Evaporators.Make the resistates that obtains after concentrating dry under vacuum, obtain faint yellow solid { 2,2,6,6-tetramethyl--3-[(4-fluorophenyl-l-base carboxamide sulfonyl) amino] piperidines-1-yl } oxyradical.

Make obtain { 2; 2; 6; 6-tetramethyl--3-[(4-fluorophenyl-l-base carboxamide sulfonyl) amino] piperidines-1-yl } oxyradical and cyanamide (1.220g; 0.029mol), EDCI (0.840g; 0.0043mol) and triethylamine (1.620ml, 0.011mol) merging in acetonitrile (20ml), and under 70 ℃, stirred 4 hours.Reaction mixture is concentrated, and dilute resistates with ethyl acetate and water (each 25ml).Collected organic layer, and concentrated at Rotary Evaporators.Then, use 10% methyl alcohol-methylene dichloride, make crude product purifying on silicagel column, obtain the oxygen base of 2-cyano group-1-(4-fluorophenyl)-3-(1-hydroxyl-2,2,6,6-tetramethyl piperidine-4-yl) guanidine, 35_a(0.248g).MS(ES⁺)m/z332.19(M+l,333.4)。

Embodiment 9. compounds 35_bSynthetic

Asscheme 1 general introduction, (0.500g, 0.0029mol) (0.490g, 0.0029mol) mixture in methylene dichloride (20ml) at room temperature stirs and spends the night with 4-chloro-phenyl-lsothiocyanates to make (4-amino-2,2,6,6-tetramethyl piperidine-1-yl) oxyradical.Reaction mixture is concentrated at Rotary Evaporators.Make the resistates that obtains after concentrating dry under vacuum, obtain faint yellow solid { 2,2,6,6-tetramethyl--3-[(4-chloro-phenyl--1-base carboxamide sulfonyl) amino] piperidines-1-yl } oxyradical.

Make obtain { 2; 2; 6; 6-tetramethyl--3-[(4-chloro-phenyl--1-base carboxamide sulfonyl) amino] piperidines-1-yl } oxyradical and cyanamide (1.220g; 0.029mol), EDCI (0.840g; 0.0043mol) and triethylamine (1.620ml, 0.011mol) merging in acetonitrile (20ml), and under 80 ℃, stirred 24 hours.Reaction mixture is concentrated, and dilute resistates with ethyl acetate and water (each 25ml).Collected organic layer, and concentrated at Rotary Evaporators.Then, use 10% methyl alcohol-methylene dichloride, make crude product purifying on silicagel column, obtain the oxygen base of 2-cyano group-1-(4-chloro-phenyl-)-3-(1-hydroxyl-2,2,6,6-tetramethyl piperidine-4-yl) guanidine, 35_b(0.415g).MS(ES⁺)m/z348.1(M+l,339.30)。

Embodiment 10. compounds 35_cSynthetic

Asscheme 3 general introductions, (0.600g 0.0035mol) at room temperature stirred 3 hours with the mixture of 4-bromophenyl lsothiocyanates (0.0035mol) in methylene dichloride (30ml) to make (4-amino-2,2,6,6-tetramethyl piperidine-1-yl) oxyradical.Reaction mixture is concentrated at Rotary Evaporators, and be suspended in ethyl acetate and the hexane (each 10ml).Cross filter solid, and dry under vacuum, obtain faint yellow solid { 2,2,6,6-tetramethyl--3-[(4-bromophenyl-1-base carboxamide sulfonyl) amino] piperidines-l-yl } oxyradical.

Make obtain { 2; 2; 6; 6-tetramethyl--3-[(4-bromophenyl-1-base carboxamide sulfonyl) amino] piperidines-l-yl } oxyradical and cyanamide (1.470g; 0.035mol), EDCI (1.0g; 0.0052mol) and triethylamine (2.00ml, 0.014mol) merging in acetonitrile (20ml), and under 75 ℃, stirred 7 hours.Reaction mixture is concentrated, and dilute resistates with ethyl acetate and water (each 25ml).Collected organic layer, and concentrated at Rotary Evaporators.Then, use 50-100% ethyl acetate-hexane, make crude product purifying on silicagel column, obtain the oxygen base of 2-cyano group-1-(4-bromophenyl)-3-(1-hydroxyl-2,2,6,6-tetramethyl piperidine-4-yl) guanidine, 35_c(0.240g).MS(ES⁺)m/z392.24(M+l,393.26)。

Embodiment 11.compounds 2 reduce to block size and myocardial damage in the rat model of Myocardial Ischemia Reperfusion Injury (MIRI)

Thirty male rats (250-300g) is anaesthetized with Thiopental Sodium, and carry out power ventilation [oxygen intake (FiO₂) mark=30%; Intermittent mandatory ventilation (IMV)=70bpm, Tidal volume (TV)=8-10ml/kg], make bandage around left anterior descending branch (LAD) coronary artery of about 1-2mm under its origin.Induce ischemic by tightening the hat suture, and kept 20 minutes.Poured into again 2 hours with realization by bandage around opening chest again and cutting coronary artery.Rat is assigned to following group (each experimental group n=10) randomly: (i) MIRI+ vehicle group: make rat stand coronary occlusion (20 minutes), and then perfusion (2 hours); (ii) the MIRI+ compound is 2 groups: make rat stand above-mentioned operative procedure, and handle with the 1mg/kg intravenous injection with compound 2, continue venoclysis with 2mg/kg/h then; And (iii) sham-operation+vehicle group: make rat except coronary occlusion, stand same operative procedure, and during Therapy lasted, keep narcosis.When 2 hours perfusion again finishes period, LAD is blocked again, and by jugular vein, 1ml Evans Blue (Evans blue) dyestuff (2% weight/volume) is injected to animal.Hazardous area (AAR) (that is, non-perfusion and therefore non-dyeing cardiac muscle) separated from non--ischemic (blueness) tissue, and be expressed as the per-cent of left ventricle.To dye the tissue from AAR that pair nitro ditetrazolium chloride is arranged and from blocking tissue, separate and weigh, and will block the per-cent that size table is shown as AAR.Compound 2 does not produce the whole body ypotension in standing the rat of MIRI, as shown in Figure 1.Significant reason is that the whole body ypotension will seriously undermine and the emphasis regions coronary ischemia.

Shown in Fig. 2 A-2B,compound 2 obviously reduces myocardium myeloperoxidase (MPO) (2A) and tissue infraction (2B).

Shown in further among Fig. 3 A-3C, though MIRI induces serious myocyte's necrosis, oedema and neutrophil infiltration (3A), but compare with sham-operation contrast (3B), again all histologic characteristicses in fact (3C) that administeredcompound 2 obviously weakens damage before the perfusion.

In with the pre-shrunk isolated rat vascular circle of norepinephrine (1 μ M) system, to find to compare with Pinacidil, compound 2 (100 μ M) is not to be effectively myocardium vessel expander, its ED₅₀Greater than logarithm of Pinacidil, show sarolemma K⁺The loss of-ATP passage activation.

Embodiment 12.compounds 2 provide protection in renal ischaemia-reperfusion injury mouse model

The kidney base of a fruit both sides that dopey male CD mouse is stoodclamp 30 minutes, and then pour into 6 hours.Shown in Fig. 4 A-4C, addcompound 2 again before the perfusion and obviously weaken blood plasma blood urea nitrogen (BUN) and creatinine (seeing 4A and 4B respectively), and kidney myeloperoxidase (MPO) (a kind of marker of neutrophil infiltration) rising (p＜0.01 pair vehicle contrast) (4C).Histological research's (not shown)announcement compound 2 provides and almost completely is protected from serious renal tubular necrosis.

Embodiment 13.compounds 2 suck in the mouse model that damages as effective rescue therapy at acute chlorine

In the environmental chamber of sealing, make male Balb/c mouse (25g; Each experimental group n=6) is exposed to 400ppm Cl in theair₂30 minutes.Cl₂Expose to finish after 15 minutes, with the ql2h scheme (peritoneal injection 30mg/kg/ dosage is in 0.5ml5% D/W [D5W]) ofcompound 2 mouse is begun experiment.In the time of 24 hours, put to death mouse, and get lung tissue to be used for by the pathologist no matter the experiment component collating look into polymorphonuclear leukocyte (PMN) soak into (as MPO level was reflected) and histology.Shown in Fig. 5 A-5B, (D5W) compares with placebo, andcompound 2 treatments reduce MPO rising (5A) and histology injury of lung (5B) 52% (p＜0.0001) and 43% (p＜0.001) respectively.

Carry out the dose-response evaluation as mentioned above, and make anamendment slightly.Compound 2 is prepared in salts solution, and at Cl₂Expose back 2 hours and 6 hours by peritoneal injection with the administration of 0.25ml volume.Find thatcompound 2 weakens pulmonary lesion in the dose-dependently mode, every kind of dosage 3mg to 80mg (or every day 6mg to 160mg) comes example as the histology score by the improvement that shows among Fig. 6.

Embodiment 14.compounds 2 do not influence glucose level

For the influence of 2 pairs of glucose levels of test compounds, to inject by intraperitoneal, the 0.25ml medicament administration that will prepare in salts solution is given the male Balb/c mouse (n=5) of heavily about 25g.Before the experiment, make themouse fasting 4 hours, and during studying, keep fasting.At specified time point, under etherization, collect 20 μ l blood samples from the tail vein, and use blood glucose meter to measure glucose level.As shown in Figure 7, compare with salt solution vehicle group,compound 2 does not show any remarkably influenced to glucose level.

Claims (31)

1. the multifunctional nitrogen oxygen derivative of a formula I:

Wherein Y be N, CH or N (→ O),

Or its enantiomer, diastereomer, racemic modification or pharmacy acceptable salt, solvate or prodrug,

Wherein

A is the part that is connected to the general formula II of any carbon atom in pyridine, phenyl or the pyridine oxide ring by its end-NH group:

X does not exist or is-(CR₂R₂)_n-;

R₁Do not exist or be 1 to 5 substituting group, each substituting group be independently selected from halogen ,-CN ,-OH ,-NO₂,-N (R₆)₂,-OCF₃,-CF₃,-OR₆,-COR₆,-COOR₆,-CON (R₆)₂,-OCOOR₆,-OCON (R₆)₂,-(C₁-C₈) alkyl ,-(C₁-C₈) alkylidene group-COOR₆,-SR₆,-SO₂R₆,-SO₂N (R₆)₂Or-S (=O) R₆, wherein said-(C₁-C₈) alkyl and-(C₁-C₈) alkylidene group-COOR₆Optionally by-OH ,-OR₃,-OCF₃,-CF₃,-COR₃,-COOR₃,-OCOOR₃,-OCON (R₃)₂,-(C₁-C₈) alkylidene group-COOR₃,-CN ,-NH₂,-NO₂,-SH ,-SR₃,-(C₁-C₈) alkyl ,-O-(C₁-C₈) alkyl ,-N (R₃)₂,-CON (R₃)₂,-SO₂R₃Or-S (=O) R₃Replace, or two adjacent R₁The carbon atom formation 5-that group is connected with them or 6-unit's carbocyclic ring or heterocycle, (C₆-C₁₀) aryl or 6-to 10-unit heteroaryl;

Each R₂Be independently selected from H, halogen ,-OCF₃,-CF₃,-OR₇,-COR₇,-COOR₇,-OCOOR₇,-OCON (R₇)₂,-(C₁-C₈) alkylidene group-COOR₇,-CN ,-NO₂,-SH ,-SR₇,-(C₁-C₈) alkyl ,-N (R₇)₂,-CON (R₇)₂,-SO₂R₇, SO₂N (R₇)₂Or-S (=O) R₇Or two R₂The carbon atom that group is connected with them forms 5-or 6-unit's carbocyclic ring or heterocycle;

Each R₃Be independently selected from (C₁-C₈) alkyl, (C₂-C₈) thiazolinyl or (C₂-C₈) alkynyl;

R₄Be selected from H ,-COOR₇,-(C₁-C₈) alkylidene group-COOR₇,-CN ,-(C₁-C₈) alkyl or-CON (R₇)₂

R₅Be selected from H ,-OH ,-O-(C₁-C₈) alkyl ,-CO-(C₁-C₈) alkyl ,-COO-(C₁-C₈) alkyl ,-CN or-NH₂

Each R₆Be independently selected from H, (C₁-C₈) alkyl, (C₃-C₁₀) cycloalkyl, 4-12-unit heterocyclic radical, (C₆-C₁₄) aryl or-(C₁-C₈) alkylidene group-NH₂

Each R₇Be independently selected from H, (C₁-C₈) alkyl ,-(C₁-C₈) alkylidene group-NH₂, (C₃-C₁₀) cycloalkyl, 4-12-unit's heterocyclic radical or (C₆-C₁₄) aryl, wherein each (except H) is optionally by-OR₆,-COR₆,-COOR₆,-OCOOR₆,-OCON (R₆)₂,-(C₁-C₈) alkylidene group-COOR₆,-CN ,-NO₂,-SR₆,-(C₁-C₈) alkyl ,-N (R₆)₂,-CON (R₆)₂,-SO₂R₆Or-S (=O) R₆Replace; And

N is integer 1 or 2.

2. multifunctional nitrogen oxygen derivative according to claim 1, wherein (i) Y is N, and A is connected to the position 2,3,4,5 or 6 of described pyridine ring; (ii) Y is CH, and A is connected to the optional position of described phenyl ring; Or (iii) Y be N (→ O), and A is connected to the position 2,3,4,5 or 6 of described 1-oxygen yl pyridines ring.

3. multifunctional nitrogen oxygen derivative according to claim 1 and 2, wherein

(i) R₁Do not exist or be 1,2,3,4 or 5, preferred 1 or 2, more preferably 1 substituting group, each substituting group be independently selected from halogen ,-OH ,-CN ,-NO₂,-N (R₆)₂,-OR₆,-OCF₃,-CF₃,-COR₆,-COOR₆,-CON (R₆)₂,-OCOOR₆,-OCON (R₆)₂,-(C₁-C₈) alkyl ,-(C₁-C₈) alkylidene group-COOR₆,-SR₆,-SO₂R₆,-SO₂N (R₆)₂Or-S (=O) R₆, each R wherein₆Be H, (C independently₁-C₈) alkyl or-(C₁-C₈) alkylidene group-NH₂, preferred H; Or

(ii) two adjacent R₁The carbon atom formation 5-that group is connected with them or 6-unit's carbocyclic ring or heterocycle, (C₆-C₁₀) aryl or 6-to 10-unit heteroaryl.

4. multifunctional nitrogen oxygen derivative according to claim 1 and 2, wherein R₂Be H.

5. multifunctional nitrogen oxygen derivative according to claim 1 and 2, wherein each R₃Be (C independently₁-C₄) alkyl, preferred (C₁-C₂) alkyl, more preferably methyl.

6. multifunctional nitrogen oxygen derivative according to claim 5, wherein R₃Be identical.

7. multifunctional nitrogen oxygen derivative according to claim 1 and 2, wherein R₄Be H.

8. multifunctional nitrogen oxygen derivative according to claim 1 and 2, wherein R₅Be-CN.

9. multifunctional nitrogen oxygen derivative according to claim 1, wherein Y is N; A is connected to the position 2,3,4,5 or 6 of described pyridine ring; R₁Do not exist or be 1 to 4 substituting group, each substituting group is halogen independently; X does not exist or is-(CR₂R₂)_n-, wherein n is 1 or 2; R₂Be H; Each R₃Be (C independently₁-C₄) alkyl, preferred (C₁-C₂) alkyl, more preferably methyl; R₄Be H; And R₅Be-CN.

10. multifunctional nitrogen oxygen derivative according to claim 9, wherein:

(i) X does not exist; R₁Do not exist; R₃It is methyl; And A is connected to the position 2,3 or 4 (this paper is designated compound 1-3) of described pyridine ring;

(ii) X does not exist; R₁Be F, Cl or Br, be connected to the position 6 of described pyridine ring; R₃It is methyl; And A be connected to described pyridine ring position 2,3,4 or 5 (this paper is designated compound 4_A-c-7_A-c);

(iii) X is-(CR₂R₂)_n-, wherein n is 1; R₁Do not exist; R₃It is methyl; And A is connected to the position 2,3 or 4 (this paper is designated compound 8-10) of described pyridine ring;

(iv) X is-(CR₂R₂)_n-, wherein n is 1; R₁Be F, Cl or Br, be connected to the position 6 of described pyridine ring; R₃It is methyl; And A be connected to described pyridine ring position 2,3,4 or 5 (this paper is designated compound 11_A-c-14_A-c);

(v) X is-(CR₂R₂)_n-, wherein n is 2; R₁Do not exist; R₃It is methyl; And A is connected to the position 2,3 or 4 (this paper is designated compound 15-17) of described pyridine ring; Or

(vi) X is-(CR₂R₂)_n-, wherein n is 2; R₁Be F, Cl or Br, be connected to the position 6 of described pyridine ring; R₃It is methyl; And A be connected to described pyridine ring position 2,3,4 or 5 (this paper is designated compound 18_A-c-21_A-c).

11. multifunctional nitrogen oxygen derivative according to claim 1, wherein Y is CH; A is connected to the optional position of described phenyl ring; R₁Do not exist or be 1 to 5 substituting group, each substituting group is halogen independently; X does not exist or is-(CR₂R₂)_n-, wherein n is 1 or 2; R₂Be H; Each R₃Be (C independently₁-C₄) alkyl, preferred (C₁-C₂) alkyl, more preferably methyl; R₄Be H; And R₅Be-CN.

12. multifunctional nitrogen oxygen derivative according to claim 11, wherein:

(i) X does not exist; R₁Do not exist; R₂Be H; And R₃Be methyl (compound 22);

(ii) X does not exist; R₃It is methyl; And R₁Be F, Cl or Br, (this paper is designated compound 23 to be connected to described phenyl ring in the position adjacent, alternate or relative with respect to A_A-c-25_A-c);

(iii) X does not exist; R₃It is methyl; And R₁Represent 2 substituting groups, each substituting group is F, Cl or Br independently, is connected to described phenyl ring in the position adjacent, alternate or relative with respect to A;

(iv) X is-(CR₂R₂)_n-, wherein n is 1; R₁Do not exist; R₂Be H; And R₃Be methyl (compound 32);

(v) X is-(CR₂R₂)_n-, wherein n is 1; R₃It is methyl; And R₁Be F, Cl or Br, (this paper is designated compound 33 to be connected to described phenyl ring in the position adjacent, alternate or relative with respect to A_A-c-35_A-c);

(vi) X is-(CR₂R₂)_n-, wherein n is 1; R₃It is methyl; And R₁Represent 2 substituting groups, each substituting group is F, Cl or Br independently, is connected to described phenyl ring in the position adjacent, alternate or relative with respect to A; Or

(vii) X is-(CR₂R₂)_n-, wherein n is 2; R₁Do not exist; R₂Be H; And R₃Be methyl (compound 36);

(viii) X is-(CR₂R₂)_n-, wherein n is 2; R₃It is methyl; And R₁Be F, Cl or Br, (this paper is called compound 37 to be connected to described phenyl ring in the position adjacent, alternate or relative with respect to A_A-c-39_A-c);

(ix) X is-(CR₂R₂)_n-, wherein n is 2; R₃It is methyl; And R₁Represent 2 substituting groups, each substituting group is F, Cl or Br independently, is connected to described phenyl ring in the position adjacent, alternate or relative with respect to A.

13. multifunctional nitrogen oxygen derivative according to claim 12, wherein X does not exist; R₃It is methyl; And R₁Represent 2 substituting groups, each substituting group is Cl, is connected to described phenyl ring (this paper is designated compound 26-31) in the position adjacent with adjacent, adjacent with alternate, adjacent with relative, alternate with alternate or alternate with relative with respect to A.

14. multifunctional nitrogen oxygen derivative according to claim 1, wherein Y be N (→ O); A is connected to the position 2,3,4,5 or 6 of described pyridine ring; R₁Do not exist or be 1 to 4 substituting group, each substituting group is halogen independently; X does not exist or is-(CR₂R₂)_n-, wherein n is 1 or 2; R₂Be H; Each R₃Be (C independently₁-C₄) alkyl, preferred (C₁-C₂) alkyl, more preferably methyl; R₄Be H; And R₅Be-CN.

15. pharmaceutical composition, it comprises according to each described multifunctional nitrogen oxygen derivative in the claim 1 to 14, or its enantiomer, diastereomer, racemic modification or pharmacy acceptable salt, solvate or prodrug and pharmaceutically acceptable supporting agent.

16. pharmaceutical composition according to claim 15, wherein said multifunctional nitrogen oxygen derivative is selected from compound 1-39.

17. pharmaceutical composition according to claim 15, its be used for intravenously, intramuscular, subcutaneous, through skin, oral, intranasal, parenteral or topical application, or be used for using by suction.

18. according to claim 17 for Orally administered pharmaceutical composition, it is the form of tablet, capsule, water-based or oily solution, suspension or emulsion.

19. the pharmaceutical composition for topical application according to claim 17, it is the form of creme, ointment, gel, water-based or oily solution or suspension, ointment, paster, gypsum, lubricant or suppository.

20. pharmaceutical composition according to claim 15, wherein said supporting agent comprises biodegradable polymkeric substance.

21. pharmaceutical composition according to claim 20 is mixed with the described multifunctional nitrogen oxygen derivative of slowly-releasing with it.

22. according to each described pharmaceutical composition in the claim 15 to 21, it is used for the treatment of disease, illness or the symptom relevant with oxidative stress or endothelial function disturbance.

23. pharmaceutical composition according to claim 22, wherein said disease, illness or the symptom relevant with oxidative stress or endothelial function disturbance are disease, illness or the symptom relevant with ischemia reperfusion injury.

24. pharmaceutical composition according to claim 23, the wherein said disease relevant with ischemia reperfusion injury, illness or symptom are selected from: septicemia, septic shock, apoplexy, cataract forms, glaucoma, ground pattern atrophy, macular degeneration, stenocardia, hemorrhagic shock, the circulation shock that superantigen is induced, renal reperfusion injury, the ephrosis that contrast medium is induced, retinopathy of prematurity, necrotizing enterocolitis, congenital alveolar dysplasia, ischemia-reperfusion lung injury, the complication of IL-2 biotherapy, myocardial infarction, the complication of cardiopulmonary bypass surgery, the limbs reperfusion injury, the erective dysfunction that the prostate excision postoperative is relevant, comprise carotid endarterectomy with vascular surgery, aortic aneurysm is repaired, the complication of perfusion again that the peripheral arterial embolectomy is relevant with thrombectomy, crush injury, the interval syndromes, organ is preserved, head trauma and Spinal injury.

25. pharmaceutical composition according to claim 22, wherein said disease, illness or the symptom relevant with oxidative stress or endothelial function disturbance are neurodegenerative diseases, for example, and Parkinson's disease, Alzheimer's and amyotrophic lateral sclerosis.

26. pharmaceutical composition according to claim 22, wherein said disease, illness or the symptom relevant with oxidative stress or endothelial function disturbance are inflammatory or immunological disease.

27. pharmaceutical composition according to claim 26, wherein said inflammatory or immunological disease are selected from: septicemia, uveitis, rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, the inflammation joint, eczema, inflammatory dermatosis, inflammatory eye disease, conjunctivitis, the tissue necrosis that is caused by inflammation, tissue rejection after the transplantation, graft versus host disease (GVH disease), Crohn's disease and ulcerative colitis, airway inflammation, asthma, bronchitis, systemic lupus erythematous, multiple sclerosis, glaucoma, the injury of lung that smoking is induced, pulmonary fibrosis, pancreatitis, myocardosis comprises the myocardosis that chemotherapy is induced, the complication of IL-2 biotherapy, diabetes, diabetic complication comprises diabetic retinopathy, peripheral neuropathy, acute macular degeneration, skin ulcer, ephrosis, pneumonia, mucositis, adult respiratory distress syndrome, cigarette sucks and skin burn.

28. pharmaceutical composition according to claim 26, wherein said inflammatory diseases are that for example chlorine, phosgene and cigarette suck the inflammatory diseases of damaging caused lung by sucking toxic agent or stimulator.

29. pharmaceutical composition according to claim 22, wherein said disease, illness or the symptom relevant with oxidative stress or endothelial function disturbance are the symptom of being correlated with chemotherapy or the radiation therapy of cancer.

30. according to each described multifunctional nitrogen oxygen derivative in the claim 1 to 14, or its enantiomer, diastereomer, racemic modification or pharmacy acceptable salt, solvate or prodrug, it is used for the treatment of disease, illness or the symptom relevant with oxidative stress or endothelial function disturbance.

31. a method that is used for the treatment of disease, illness or the symptom relevant with oxidative stress or endothelial function disturbance, described method comprise to the individual administering therapeutic significant quantity that needs are arranged according to each described multifunctional nitrogen oxygen derivative or its enantiomer, diastereomer, racemic modification or pharmacy acceptable salt, solvate or prodrug in the claim 1 to 14.

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